Article Text

Download PDFPDF

Improving the Helsinki Declaration's guidance on research in incompetent subjects
  1. Anna Eva Westra,
  2. Inez de Beaufort
  1. Department of Medical Ethics and Philosophy of Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands
  1. Correspondence to Dr Anna Eva Westra, Department of Medical Ethics and Philosophy of Medicine, Erasmus University Medical Centre, PO box 2040, Rotterdam 3000 CA, The Netherlands; a.e.westra{at}lumc.nl

Abstract

Research involving children or other incompetent subjects who are deemed unable to provide informed consent is complex, particularly in the case of research that does not directly benefit the research subjects themselves. The Helsinki Declaration, the World Medical Association's landmark document for research ethics, therefore states that incompetent research subjects must not be included in such research unless it entails only minimal risk and minimal burden. In this paper, we argue that now that research in these groups is expected to expand, this undifferentiated minimal risk and burden requirement does not suffice any more. In the upcoming revision of the Declaration, the paragraph at stake should be refined in such a way that it is not unnecessarily restrictive or more permissive than can be ethically justified. Our first recommendation is to stimulate research ethics committees to identify more accurately those risks and burdens that the research subjects must undergo solely for research purposes by distinguishing between two types of study procedures instead of between two types of studies. Our second recommendation is to allow for exceptions to the minimal risk and burden requirement in cases of exceptionally valuable studies that involve subjects who can give their assent to participate in the study and that involve at most a minor increase over minimal risk and/or burden.

  • Research Ethics
  • Children
  • Ethics Committees/Consultation
  • Clinical trials
  • Competence/incompetence

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Conducting research that involves children or other persons who are incompetent to provide informed consent is ethically complex, particularly in the case of research that cannot directly benefit the research subjects themselves (also known as ‘non-therapeutic research’). The Helsinki Declaration, the World Medical Association's landmark document for research ethics, therefore includes a special paragraph concerning the acceptable levels of risk and burden in such research. Paragraph 27 states that incompetent research subjects ‘must not be included in a research study that has no likelihood of benefit’ unless the study ‘entails only minimal risk and minimal burden’.1 In this paper, we will argue why this paragraph should be refined in the upcoming revision of the Declaration. We will briefly explain the ethical dilemma that paragraph 27 addresses and then argue why the time has come for a refinement of two issues.

The ethical dilemma

Research involving human subjects can be conducted only after a research ethics committee has determined whether all requirements for ethical research are fulfilled.2 In the case of research involving children or other persons who are incompetent to provide informed consent, the committee's task is more complex, particularly if the research cannot directly benefit the research subjects, which significantly increases the risk of exploitation. The main reason for this increased complexity is that usually, if a study fulfils all other requirements for ethical research, the subject's informed consent to participate in a study makes it ethically acceptable that he or she is exposed to risks and burdens solely for research purposes. For, if someone voluntarily chooses to participate based upon a clear appreciation and understanding of what this will comprehend, this person is in charge rather than being exploited. When the research involves subjects who are unable to decide how much risk or burden they are willing to undergo solely for research purposes, such reasoning is not possible. Although the legally authorised representatives are asked to provide proxy consent, that can never fully replace the truly personal consent one would aim to receive in a research setting.

On the other hand, involving children and other incompetent people in non-therapeutic research is essential to improve care for future patients in these groups. Unfortunately, not all necessary data can be obtained within a therapeutic design. Typical examples of non-therapeutic research are pharmacokinetic measurements and research investigating pathophysiological mechanisms. Although such researches often form essential steps towards developing a diagnostic test or treatment for a disease, the subjects usually do not directly benefit from participation. Thus, a complete ban on involving children or other incompetent subjects in non-therapeutic research could seriously harm future patients.

Why now time has come for a refinement

The minimal risk option that is present in the Helsinki Declaration as well as in many other guidelines and regulations provides an elegant solution to the dilemma.3–5 Most ethicists agree that this approach is compatible with the aim of providing adequate protection for incompetent subjects, because exposing incompetent subjects to risks and burdens solely for research purposes can be justified if these risks and burdens are very low (provided that adequate definitions of the concepts of ‘minimal risk’ and ‘minimal burden’ are available and used).6–8

However, the Helsinki Declaration does not yet provide optimal guidance. The relevant paragraph is based on a questionable distinction between two types of studies and does not distinguish between various degrees of incompetence. Until recently, this posed less of a problem; partly due to the ethical concerns and partly due to financial and practical concerns, the number of proposals for research in incompetent subjects was relatively low. However, as a consequence of patent-related stimulation programmes in both the USA and the European Union, the number of proposals now are increasing, particularly in the field of paediatrics.9–11 Not surprisingly, some of the recent proposals seem to have more to do with market considerations than with the needs of patients.12 ,13 This makes it all the more pressing to refine the system that protects incompetent research subjects in such a way that it is neither unnecessarily restrictive nor more permissive than can be ethically justified.

Recommendation 1: encouraging procedure-level risk-benefit assessment

The first issue that must be addressed is that paragraph 27 is based on a distinction between two types of studies. This distinction is based on the idea that whereas research subjects in non-therapeutic studies face risks and burdens solely for research purposes, this is never the case during therapeutic studies. However, in reality, many so-called therapeutic studies are more complex. For example, consider phase III randomised controlled trials. Usually, in addition to taking the trial drug (or standard therapy or placebo), the participants of such trials must undergo several procedures solely for research purposes. These procedures may range from blood sampling, puberty staging or MRI scans to bone marrow biopsies in the case of oncology studies. In addition, some studies involve a washout or non-medication phase; that is, a period during which the subjects do not receive any treatment even though established therapy is available. All of these procedures involve some risks and/or burdens; some can be regarded as minimal, but this is not necessarily always the case.

When performing study-level risk-benefit assessment, research ethics committees are insufficiently focused on the fact that a therapeutic study may involve such non-therapeutic procedures. This lack of focus is problematic for two reasons. First, as long as committees do not identify these procedures as being performed solely for research purposes, they are unlikely to evaluate them as such (ie, they are unlikely to assess whether or not the risks and burdens at stake can be regarded as minimal). Hence, they may unintentionally let incompetent subjects be exposed to unacceptably high risks or burdens. Second, such unawareness may compromise the informed consent procedure; when aiming for a valid informed consent process, it seems vital that the subjects and their representatives are told which of the research risks and burdens they must undergo solely for research purposes.

The solution to these problems is to start using a distinction between two types of procedures instead of between two types of studies. Such an approach is not new: already since 1983, the relevant paragraph in the US Federal Regulations has referred to procedures rather than studies.3 Moreover, in 1999, Levine argued that the distinction between two types of studies was a serious error in the Helsinki Declaration.14 In the past few years, both Weijer et al and Wendler et al have proposed specific methods for implementing procedure-level risk-benefit assessment.15–17

Recommendation 2: allowing higher levels of risk and burden for subjects who can give assent

The second issue that we would like to see addressed is that paragraph 27 does not distinguish between those incompetent subjects who are considered capable of giving their assent to participate in a study and those who are considered unable to do so. Assent is usually described as the positive agreement that should be obtained from incompetent subjects who are considered generally capable of understanding the study, of understanding the risks and burdens they must face and of making their own decisions based on this knowledge, in addition to the proxy consent of the legally authorised representative. Assent is a well-known concept; almost all guidelines and regulations, including the Declaration of Helsinki, address it in their informed consent paragraphs.

It is quite remarkable that in paragraph 27 the concept of assent does not play a role. Please remember that the requirement of minimal risk and burden was established because incompetent subjects are at risk of exploitation as they are deemed unable to decide how much risk or burden they are willing to undergo solely for research purposes. If the subjects at stake are generally capable of understanding the study, of understanding the risks and burdens they must face and of making their own decisions based on this knowledge, the risk of exploitation seems significantly lower than if the subjects do not understand anything at all. Thus, we would say, research ethics committees should not treat these two types of incompetent subjects alike. In the case of research with incompetent subjects who are considered capable of giving their assent to participate in the study, they could be a bit more permissive regarding the acceptable levels of risk and burden.17

We realise that assent acknowledges the developing or partial decision-making capacity of the incompetent subject, which means that those who are able to give assent still require more protection than competent adults. Therefore, we recommend only allowing exceptions to the minimal risk and burden requirement in the case of research involving subjects that can give assent (in addition to the proxy consent) if the research involves at most a minor increase over minimal risk and/or burden, aims for indispensible data and encompasses the optimal balance between scientific rigour and an optimal risk-benefit ratio for the research subjects.18

We also realise that to date, no consensus exists on how to determine which incompetent persons should be regarded capable of providing assent and which are not.19–21 Please note that when implementing our proposal, it is important to reserve the term assent for the positive agreement of those subjects who can be involved in the decision-making process in a truly meaningful way. Of course, when subjects cannot be involved in such a meaningful way, talking with them about what is going to happen is also very important, but such involvement, in our view, should not be called assent.

Concluding remarks

The World Medical Association, the organisation that issues the Declaration of Helsinki, is planning another revision of this influential research ethics guidance document. We recommend that paragraph 27, which addresses research with incompetent research subjects, be refined on two points. One could object that following our two recommendations would be too time-consuming as research ethics committees are often already heavily overloaded. We acknowledge that this may be the case, especially in complex cases. However, we believe that such complex studies in particular deserve this investment of time. Facilitating research in children and other incompetent subjects is extremely important; however, exposing incompetent subjects to risks and burdens solely for research purposes must always be regarded as a last resort.

Paragraph 27 of the Declaration of Helsinki

For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject, the research cannot instead be performed with competent persons and the research entails only minimal risk and burden.

Paragraph 27: proposed revision

For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in studies involving procedures that have no likelihood of direct benefit for them unless these procedures are intended to promote the health of the population represented by the potential subject, cannot instead be performed with competent persons and all together entail only minimal risk and minimal burden. In case of exceptionally valuable studies involving incompetent subjects who are able to give their assent to participate in the study, the procedures that have no likelihood of direct benefit may entail at most a minor increase over minimal risk and/or burden.

Acknowledgments

We are grateful for the helpful comments on earlier drafts of this manuscript by Karin Jongsma and by the attendants of a conference called ‘The future of the Declaration of Helsinki’, on 26 June 2012, in Rotterdam, the Netherlands.

References

Footnotes

  • Contributors AW is a paediatric resident at the Juliana Children's Hospital (The Hague, the Netherlands), as well as a part-time postdoctoral researcher at the department of Medical Ethics of the Erasmus Medical Center Rotterdam. In 2011, she defended her PhD thesis on the ethical issues of medical research in children. She proposed and performed this analysis and drafted the manuscript. IdB is professor of Medical Ethics at Erasmus Medical Centre Rotterdam. Since her PhD in 1981 on research with human subjects, she has been involved in the debate as well as the practice of ethical review of research. She reviewed the analyses and initial draft of the manuscript and provided essential critical comments. Both authors reviewed the final version of the manuscript. AW is the guarantor, has full access to all of the data used in this analysis, and takes responsibility for the accuracy of the data analysis.

  • Funding The Netherlands Organisation for Health Research and Development (grant number 92003475).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Other content recommended for you