Informed consent and phase IV non-interventional drug research

Abstract

Most of the literature on informed consent in pharmaceutical drug research works on the assumption that informed consent is something that is homogeneous and thus can be rendered procedurally universal. This may be justifiable to a certain extent owing to the fact these are all drug trials anyway. Nevertheless, in spite of this general similarity, we also know that the clinical drug development phases are characteristically different, and that phase IV is very different from the other phases because, owing to its postmarketing nature, it is much more varied in scope and in type. Thus, it is worthwhile looking into the ethical nuances relevant to the informed consent process in phase IV non-interventional drug research. We shall deal with the issues on the necessity of informed consent for this type of research and then discuss the possibilities for an opt-out system. We conclude that informed consent is necessary for non-interventional studies, and thus any form of waiving of rights of participants to informed consent must have a valid substantial justification. The distinct character of phase IV accounts for the difference in content of the informed consent document compared to that of earlier phases, and both opt-in and opt-out procedures are ethically justifiable as long as the participant’s participation remains informed and voluntary.

Key words::

• Consent forms
• Informed consent
• Non-interventional studies
• Observational studies
• Phase IV
• Research ethics

Transparency

Declaration of funding

This study was carried out within the context of the Escher project (T6-202), a Dutch Top Institute Pharma project. R.B.’s PhD project is funded by Dutch Top Institute Pharma.

Declaration of financial/other relationships

J.R. works and holds stock in GlaxoSmithKline, the Netherlands. R.B., G.v.T, and J.v.D have no financial or other relevant relationships to declare.

No assistance in the preparation of this article is declared.

Notes

*The terms ‘study’ and ‘trial’ are interchangeable.

†Directive 2001/20/EC, which puts forth European Union regulation on good clinical practice of clinical trials, defines a clinical trial as ‘any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify and adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy’5. This directive distinguishes a clinical trial from an NIS as defined above, and thus the directive on clinical trials clearly states in Article 1 (1) that NIS are excluded from the scope of the directive: ‘This Directive does not apply to non-interventional trials’5. As such, at least legally, there is a distinction between a ‘clinical trial’ and an NIS.

*Generic rights are rights of agents as agents, i.e. no agency is possible without the perfect fulfilment of such rights. ‘The generic conditions of agency consist of what vulnerable agents need, irrespective of what their purposes might be, in order to be able to act at all or in order to be able to act with general chances of success’20.

†Based on the American Common Rule, the conditions which all must be met are as follows: (a) the research involves no more than minimal risk; (b) the waiver or alteration will not adversely affect the rights and welfare of the subjects; (c) the research could not practicably be carried out without the waiver or alteration; and (d) whenever appropriate, the subjects will be provided with additional pertinent information after participation22.

*Therapeutic misconception ‘ involves a research participant’s failure to recognise how personal care (i.e., the obligation of physicians to make medical decisions solely with the patient’s interest in mind) may be compromised by research procedures…this core concept of TM could be manifest in two ways: (1) when participants express an incorrect belief that their individualised needs will determine assignment to treatment conditions or lead to modification of the treatment regimen (TM₁); or (2) when participants offer an unreasonable appraisal of the nature or likelihood of medical benefit from participation in the study, due to a misperception of the research enterprise (TM₂)26.