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The American Journal of Bioethics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uajb20
Open-Label Extension Studies: Are They Really Research? a
Mildred K. Cho a
Stanford University Published online: 14 Apr 2014.
Click for updates To cite this article: Mildred K. Cho (2014) Open-Label Extension Studies: Are They Really Research?, The American Journal of Bioethics, 14:4, 60-61, DOI: 10.1080/15265161.2014.889958 To link to this article: http://dx.doi.org/10.1080/15265161.2014.889958
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
The American Journal of Bioethics
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3. As to whether the drug company or sponsor of the study has an ethical obligation to continue treating the secondary pulmonary hypertension cohort—in the absence of clear consensus (and there is no consensus in this case)—there is no obligation. But if studying this group offers relative safety for the subjects; asks a reasonable, unresolved scientific question with clinical significance; and subjects are willing to continue in the trial, then continuing seems like a prudent idea.
Cherry, M. J. 2009. UNESCO, ‘universal bioethics,’ and state regulation of health risks: A philosophical critique. Journal of Medicine and Philosophy 34(3): 274–295. Engelhardt, H. T. 1996. The foundations of bioethics, 2nd ed. 4-40, 124–128. 330–336. New York, NY: Oxford University Press. Faden, R. R., and T. L. Beauchamp. 1986. A history and theory of informed consent. 274–294. New York, NY: Oxford University Press. Freedman, B. 1987. Equipoise and the ethics of clinical research. The New England Journal of Medicine 317(3): 141–145.
REFERENCES
Shaw, L. W., and T. C. Chalmers. 1970. Ethics in cooperative clinical trials. Annals of the New York Academy of Sciences 169: 487–495. doi: 10.1111/j.1749-6632.1970.tb54759.x.
Anderson, J. A. 2010. Clinical research in context: Reexamining the distinction between research and practice. Journal of Medicine and Philosophy 35(1): 46–63.
Trotter, G. 2009. The UNESCO declaration on bioethics and human rights: A canon for the ages?. Journal of Medicine and Philosophy 34(3): 195–203.
Open-Label Extension Studies: Are They Really Research? Mildred K. Cho, Stanford University This consultation about the open-label extension phase of a drug trial raises at least two related questions. The first was posed by the requestor of the consultation: Should the sponsor of this clinical trial mandate that subgroups of subjects for whom the trial had so far shown no benefit discontinue use of the drug now that the study is in the open-label phase, or merely inform subjects and the participating physicians about the findings? Second, does the sponsor have an obligation to allow interested subjects to remain in the trial at no cost? Central to this case is the assessment of risks and benefits of the intervention. However, the analysis is dependent on whether the primary purpose of the activity (the openlabel extension phase of the study) is to create generalizable knowledge (i.e., research) or to provide clinical benefit according to the needs of individuals enrolled in the study (i.e., compassionate use). The usefulness of open-label extension studies for generating reliable and valid data has been challenged (Day and Williams 2007), even as they become more common, and their real purpose is somewhat ambiguous. Therefore, clarification of the intentions of the sponsor is important to the ethical analysis. Several ethical concerns of open-label studies have been highlighted, primarily that the prospect of receiving interventions that would otherwise not be available or only available at high cost to the subject is coercive (Micetich 1996), especially for subjects with serious and/or terminal illnesses. Indeed, 80% of subjects interviewed in a study
(n = 32) conducted in a pain clinic reported that availability of study medications after hypothetical clinical trials would be an important factor in deciding whether to participate (Cassarett et al. 2001). In addition, some have argued that subjects cannot give informed consent to participate in an open-label extension study unless they know to which arm of the main trial they were assigned (Wainwright 2002). Irrespective of the purpose of the activity, clinicians and subjects should be informed of the results and of any concerns the study has generated. If the purpose of the activity is primarily research, federal regulations for protection of human subjects (45 CFR 46) require that risks be balanced by benefits. Data from the Cassarett study suggest that research subjects see potential benefit to themselves in the option to continue to take medications in an open-label extension phase of a study (Cassarett et al 2001) and that the data may “expand the range of normative judgments about open label studies” based on subject preferences. Nevertheless, if this primarily is considered a research activity, this particular trial should be discontinued for all patients because the benefits from generalizable knowledge would be very limited given this study design. In other words, researchers do not have an obligation to provide a drug as part of an open-label extension that is not effective. Ideally, this should have been made clear in the consent form. If the purpose is primarily to provide clinical benefit to individuals, however, the sponsor should continue to
Address correspondence to Mildred K. Cho, Stanford University, 1215 Welch Road, ModA, Stanford, CA 94305, USA. E-mail: micho@ stanford.edu
60 ajob
April, Volume 14, Number 4, 2014
Research Ethics
REFERENCES Cassarrett, D., J. Karlawish, P. Sankar, K. B. Hirschman, and D.A. Asch. 2001. Open label extension studies and the ethical design of clinical trials. IRB: Ethics & Human Research 4: 1–5. Day, R. O., and K. M. Williams. 2007. Open-label extension studies: Do they provide meaningful information on the safety of new drugs? Drug Safety 30: 93–105. Micetich, K. C. 1996. The ethical problems of the open label extension study. Cambridge Quarterly of Healthcare Ethics 5: 410–414. Taylor, G. J., and P. Wainwright. 2005. Open label extension studies: research or marketing?British Medical Journal 331: 572–574. Wainwright, P. 2002. Consent to open label extension studies: some ethical issues. Journal of Medical Ethics 28: 373–376.
Downloaded by ["University at Buffalo Libraries"] at 05:11 03 March 2015
provide access to the drug under the same conditions as in the main study (e.g., at no cost to subjects). Subjects’ participation in the trial could be continued at the discretion of subjects and their physicians, assuming that they know in which arm of the main study they had participated. Thus, the research framework should not be used to guide the assessment of risks and benefits (Taylor and Wainwright 2005). However, the researchers could collect data to aid future study designs, such as whether individual subjects experience significant benefit other than the main study’s surrogate endpoints (e.g., 6-minute walking distance), or whether physicians believe that there are clinically important benefits of the intervention, such as potentially providing a bridge to transplant.
April, Volume 14, Number 4, 2014
ajob 61
The American Journal of Bioethics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uajb20
Open-Label Extension Studies: Are They Really Research? a
Mildred K. Cho a
Stanford University Published online: 14 Apr 2014.
Click for updates To cite this article: Mildred K. Cho (2014) Open-Label Extension Studies: Are They Really Research?, The American Journal of Bioethics, 14:4, 60-61, DOI: 10.1080/15265161.2014.889958 To link to this article: http://dx.doi.org/10.1080/15265161.2014.889958
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
The American Journal of Bioethics
Downloaded by ["University at Buffalo Libraries"] at 05:11 03 March 2015
3. As to whether the drug company or sponsor of the study has an ethical obligation to continue treating the secondary pulmonary hypertension cohort—in the absence of clear consensus (and there is no consensus in this case)—there is no obligation. But if studying this group offers relative safety for the subjects; asks a reasonable, unresolved scientific question with clinical significance; and subjects are willing to continue in the trial, then continuing seems like a prudent idea.
Cherry, M. J. 2009. UNESCO, ‘universal bioethics,’ and state regulation of health risks: A philosophical critique. Journal of Medicine and Philosophy 34(3): 274–295. Engelhardt, H. T. 1996. The foundations of bioethics, 2nd ed. 4-40, 124–128. 330–336. New York, NY: Oxford University Press. Faden, R. R., and T. L. Beauchamp. 1986. A history and theory of informed consent. 274–294. New York, NY: Oxford University Press. Freedman, B. 1987. Equipoise and the ethics of clinical research. The New England Journal of Medicine 317(3): 141–145.
REFERENCES
Shaw, L. W., and T. C. Chalmers. 1970. Ethics in cooperative clinical trials. Annals of the New York Academy of Sciences 169: 487–495. doi: 10.1111/j.1749-6632.1970.tb54759.x.
Anderson, J. A. 2010. Clinical research in context: Reexamining the distinction between research and practice. Journal of Medicine and Philosophy 35(1): 46–63.
Trotter, G. 2009. The UNESCO declaration on bioethics and human rights: A canon for the ages?. Journal of Medicine and Philosophy 34(3): 195–203.
Open-Label Extension Studies: Are They Really Research? Mildred K. Cho, Stanford University This consultation about the open-label extension phase of a drug trial raises at least two related questions. The first was posed by the requestor of the consultation: Should the sponsor of this clinical trial mandate that subgroups of subjects for whom the trial had so far shown no benefit discontinue use of the drug now that the study is in the open-label phase, or merely inform subjects and the participating physicians about the findings? Second, does the sponsor have an obligation to allow interested subjects to remain in the trial at no cost? Central to this case is the assessment of risks and benefits of the intervention. However, the analysis is dependent on whether the primary purpose of the activity (the openlabel extension phase of the study) is to create generalizable knowledge (i.e., research) or to provide clinical benefit according to the needs of individuals enrolled in the study (i.e., compassionate use). The usefulness of open-label extension studies for generating reliable and valid data has been challenged (Day and Williams 2007), even as they become more common, and their real purpose is somewhat ambiguous. Therefore, clarification of the intentions of the sponsor is important to the ethical analysis. Several ethical concerns of open-label studies have been highlighted, primarily that the prospect of receiving interventions that would otherwise not be available or only available at high cost to the subject is coercive (Micetich 1996), especially for subjects with serious and/or terminal illnesses. Indeed, 80% of subjects interviewed in a study
(n = 32) conducted in a pain clinic reported that availability of study medications after hypothetical clinical trials would be an important factor in deciding whether to participate (Cassarett et al. 2001). In addition, some have argued that subjects cannot give informed consent to participate in an open-label extension study unless they know to which arm of the main trial they were assigned (Wainwright 2002). Irrespective of the purpose of the activity, clinicians and subjects should be informed of the results and of any concerns the study has generated. If the purpose of the activity is primarily research, federal regulations for protection of human subjects (45 CFR 46) require that risks be balanced by benefits. Data from the Cassarett study suggest that research subjects see potential benefit to themselves in the option to continue to take medications in an open-label extension phase of a study (Cassarett et al 2001) and that the data may “expand the range of normative judgments about open label studies” based on subject preferences. Nevertheless, if this primarily is considered a research activity, this particular trial should be discontinued for all patients because the benefits from generalizable knowledge would be very limited given this study design. In other words, researchers do not have an obligation to provide a drug as part of an open-label extension that is not effective. Ideally, this should have been made clear in the consent form. If the purpose is primarily to provide clinical benefit to individuals, however, the sponsor should continue to
Address correspondence to Mildred K. Cho, Stanford University, 1215 Welch Road, ModA, Stanford, CA 94305, USA. E-mail: micho@ stanford.edu
60 ajob
April, Volume 14, Number 4, 2014
Research Ethics
REFERENCES Cassarrett, D., J. Karlawish, P. Sankar, K. B. Hirschman, and D.A. Asch. 2001. Open label extension studies and the ethical design of clinical trials. IRB: Ethics & Human Research 4: 1–5. Day, R. O., and K. M. Williams. 2007. Open-label extension studies: Do they provide meaningful information on the safety of new drugs? Drug Safety 30: 93–105. Micetich, K. C. 1996. The ethical problems of the open label extension study. Cambridge Quarterly of Healthcare Ethics 5: 410–414. Taylor, G. J., and P. Wainwright. 2005. Open label extension studies: research or marketing?British Medical Journal 331: 572–574. Wainwright, P. 2002. Consent to open label extension studies: some ethical issues. Journal of Medical Ethics 28: 373–376.
Downloaded by ["University at Buffalo Libraries"] at 05:11 03 March 2015
provide access to the drug under the same conditions as in the main study (e.g., at no cost to subjects). Subjects’ participation in the trial could be continued at the discretion of subjects and their physicians, assuming that they know in which arm of the main study they had participated. Thus, the research framework should not be used to guide the assessment of risks and benefits (Taylor and Wainwright 2005). However, the researchers could collect data to aid future study designs, such as whether individual subjects experience significant benefit other than the main study’s surrogate endpoints (e.g., 6-minute walking distance), or whether physicians believe that there are clinically important benefits of the intervention, such as potentially providing a bridge to transplant.
April, Volume 14, Number 4, 2014
ajob 61
