Ethical issues in postauthorization drug trials

Abstract

This thesis is an attempt to raise some ethical issues that are specific to phase IV drug trials and to provide preliminary responses to such issues. We limited ourselves to issues of informed consent, risk-benefit assessment, and the therapeutic orientation of phase IV. On the issue of informed consent (IC) and phase IV, we deliberated on issues related to form and procedure. First, we demonstrated that in phase IV non-interventional studies, though IC remains the standard, the manner of collecting and the content of the IC form differ from those of the earlier phases. Also, given the presence of a substantive justification, waiving of IC may be ethically acceptable in “exceptional” circumstances. We then looked at phase IV studies where the only intervention is the randomization of the participants in terms of the trial drug and the comparators while the other procedures remain “standard clinical practice”. In these studies, the waiving of IC is not ethically defensible, though an opt-out procedure may be justifiable in cases of minimal risk. Lastly, we looked at the case of collecting IC of psychiatric patients for the biobanking of their blood for both clinical use and pharmacogenetic research. In the case of the latter, neither the waiving of IC nor an opt-out procedure is justifiable. After the ethical reflection on IC, we then looked at the applicability of decision theory methods in the balancing of benefits and risks (B&R) in clinical trials. We first raised the issue of the need for clarity and reasonableness in the balancing of B&R. Next, we looked at the procedure-level approaches in research ethics. We concluded that conflation is the source of difficulty with these methods; we also demonstrated that research ethics would benefit from incorporating decision theory methods in the various (B&R) weighing tasks. Lastly, we focused on the B&R evaluation task of IRBs and showed that expected utility theory may aid in making the weighing task explicit and less intuitive. The third part of the thesis dealt with the therapeutic orientation of phase IV. Given the assumptions that phase IV trials should typically aim at informing a clinical decision and that the value of a phase IV trial hinges on its clinical relevance, we looked at the current state of phase IV non-inferiority trials. We realized that though half of the post-authorization NI trials we studied reported additional benefit claims, these claims are seldom supported by sufficient data and formal testing to establish statistical significance. After demonstrating that the design of post-authorization non-inferiority studies ought to be improved in terms of ensuring clinical value and providing evidence for it, we explored the question of the fiduciary obligation of the physician researcher in phase IV interventional studies. We showed that since phase IV trials are by nature, purpose, and setting closer to practice that the other phases of drug development, physician-researchers are primarily physicians and secondarily researchers whose fiduciary obligation to their patient-participants remains, though some aspects of this obligation may have been waived.