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Acceptable risks and burdens for children in research without direct benefit: a systematic analysis of the decisions made by the Dutch Central Committee
  1. Anna E Westra1,
  2. Rám N Sukhai1,
  3. Jan M Wit1,
  4. Inez D de Beaufort2,
  5. Adam F Cohen3
  1. 1Leiden University Medical Center, Department of Paediatrics, Leiden, The Netherlands
  2. 2Erasmus University Medical Center, Department of Medical Ethics and Philosophy of Medicine, Rotterdam, The Netherlands
  3. 3Department of Clinical Pharmacology Center for Human Drug Research, Leiden, the Netherlands
  1. Correspondence to Anna E Westra, Leiden University Medical Center, Department of Paediatrics, Albinusdreef 2, P.O.box 9600, 2300 RC Leiden, The Netherlands; a.e.westra{at}lumc.nl

Abstract

Objectives To evaluate whether the requirement of “minimal risk and burden” for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk.

Design and setting Systematic analysis of the approval/rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO).

Review methods The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit.

Results 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved.

Conclusions The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.

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Introduction

The involvement of children in research that will not directly benefit them poses an ethical dilemma. Considering the assumption that children cannot give full consent, it is not easy to justify research risks and burdens that are not compensated by direct benefits for the participating children themselves.1 On the other hand, without such research, some data necessary for improving paediatric care will never be available. Hence, the central dilemma is how to allow for research that benefits children as a group rather than the individual participants, without jeopardising the integrity or safety of the participants.

The most common solution for this dilemma is to allow all paediatric research without direct benefit that can show that the risks and burdens are below a certain limit. Until recently, the European Convention on Human Rights and Biomedicine and the Declaration of Helsinki provided the only ethical guidance recognised in Europe, namely that the risks and burdens in such research may never be more than “minimal”.2 3 “Minimal risk” and “minimal burden” are absolute criteria: in the Additional Protocol to the Convention, minimal risk is defined as “a very slight and temporary negative impact on the health of the person concerned”, and minimal burden as discomfort that is “at the most, temporary and very slight”.4

Over the last few years, the call for more medical research involving children has raised the question of whether a regulatory framework based on the requirement of minimal risk and burden might be too restrictive.5 6 To address this concern, in a recent document that provides guidance on the application of the Clinical Trials Directive with regard to trials with minors, the EU recommended allowing “a minor increase over minimal risk” for all studies that may provide benefit to the group of children with the same disease.7 8

To our knowledge, no empirical data have been published that show whether the requirement of “minimal risk and burden” indeed compromises the ability to obtain data necessary for improving paediatric care and, hence, should be reconsidered.9 In order to provide relevant data, we systematically analysed the decisions to approve or reject proposals presented to the Dutch Central Committee on Research Involving Human Subjects (CCMO). The requirement of minimal risk and burden for paediatric studies without direct benefit has been incorporated into Dutch civil law, and during the past 9 years, most proposals of this type were reviewed by this central committee; this created a unique situation for our project.10

Methods

The Dutch Central Committee on Research Involving Human Subjects (CCMO)

The CCMO was instituted when the Dutch Medical Research with Human Subjects Law went into operation in 1999 and is based in The Hague, the Netherlands.10 Among its 14 members are experts in paediatrics, pharmacology, law, methodology and ethics. The committee's broad range of tasks includes accrediting institutional Research Ethics Committees and, in specific cases, reviewing research protocols.9 An important category of protocols that are, on a mandatory basis, reviewed by this central committee are paediatric intervention studies without direct benefit; that is, studies that deliberately alter the condition of the subjects (in order to evaluate the effects of an intervention) without providing direct benefit to them.11

Inclusion criteria

We analysed all proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. This included all intervention studies without direct benefit and all observational studies (this type of study was reviewed by the committee between 2002 and 2005).11 The committee considers drug trials to be without direct benefit in case they fit within the early phases (phase I and occasionally phase II) of a pharmaceutical drug development plan or if they aim to acquire more knowledge about the age-related pharmacokinetics and pharmacodynamics of commonly (although often unlicensed or off label) prescribed drugs—for example, dexamethasone.

Data collection

We recorded the following characteristics of the proposed research projects: initiator, interventional or only observational, number of (Dutch) participants needed, health status and age of participants to be involved and procedure(s) to be performed. The decisions made by the CCMO and its rationale were obtained from committee member reports, committee meeting minutes and subsequent correspondence with researchers. For the purpose of this analysis, we defined “approved” as permission to conduct the study as originally proposed. “Rejected” was defined as no permission. The protocols that had to be discussed more than once and were only “approved after revision” formed the third category. Some, but not all, of these studies required essential modifications before they could be approved. In case of rejection, the reasons for the decision were obtained from the rejection letter. Studies that were submitted twice (after rejection, submitted for a second review) were considered “resubmissions”. Studies that had not been resubmitted at the end of our inclusion period, or that were rejected again, and consequently could not be conducted, were classified as “definitively rejected”.

Analysis

A descriptive analysis of the data was performed. First, all protocols were classified according to their objectives. Second, all reasons for requiring essential modifications or for rejection were categorised by whether they were based on the requirement of minimal risk and burden, the requirement of group relatedness (ie, that it would not be possible to conduct the study in adults) or the more general criteria for ethical research (eg, scientific value and validity, provision of appropriate informed consent and assent procedures).12 All studies with risks and/or burdens that were considered to exceed the minimal level, whether approved after essential modifications or rejected, were categorised by type of study. Subsequently, to shed more light on the committee's interpretations of “minimal risk” and “minimal burden”, we analysed in more detail the review process resulting in the decisions on all studies of the most homogenous subgroup, that is, the drug studies.

Results

During the 7.5-year period analysed, the CCMO reviewed 165 proposals for paediatric research without direct benefit. The characteristics of the studies are shown in table 1. Of the 165 proposed studies, 111 were observational studies and 54 were intervention studies. The observational studies involved a wide variety of invasive procedures, including venipuncture, and/or blood sampling from a pre-existing intravenous (IV) cannula, psychologically invasive questionnaires, MRI, measurements of anal sphincter pressure, airway hyperreactivity challenges, biopsies and bone marrow punctures (in children anaesthetised for clinical reasons). Of the intervention studies, 27 were drug studies: 18 early phase drug studies and nine studies with pharmacokinetic and/or pharmacodynamic objectives outside a drug development plan.

Table 1

Characteristics of the studies

All studies: approval/rejection decisions

Of the 165 proposed studies, 30 required and underwent essential modifications before they could be approved and 45 were rejected (figure 1). The requirement of minimal risk and burden was cited as one of the reasons for 38 of these 75 decisions (figure 1; table 2). In 20 of the 38 cases, the study was approved after the investigators modified the protocol to reduce the risk and/or burden. For instance, a human papilloma virus vaccine study was approved on condition that no gynaecological exams would be performed in minors. Another study, aimed at identifying predictors for gastro-oesophageal reflux disease in severely disabled children, was approved after omission of the rectal examinations. Four studies that involved MRI scanning were only approved for children over 8 years old, for whom the burden was considered to be minimal. The other 18 of the 38 studies were rejected. Six of these 18 studies were approved after appeal, resubmission of a modified protocol or revision during the second review process (figure 1). One was again rejected, but for reasons unrelated to risk or burden. Eleven studies were definitively rejected due to risks and/or burdens exceeding the minimal level. In three of these 11 cases (including two early phase drug studies), the requirement of minimal risk and burden was cited as the only reason for rejection.

Figure 1

The committee's decisions on the 165 protocols.

Table 2

Reasons for approval/rejection decisions*

Drug studies: in-depth analysis

To shed more light on the committee's interpretations of “minimal risk” and “minimal burden”, we analysed in more detail the review process resulting in the decisions on all studies of the most homogenous subgroup, that is, the 27 drug studies.

Regarding “minimal risk”, the CCMO mainly looked at the adverse effects of the drug to be tested. In most of the 20 studies that were considered to involve “minimal risk”, the study drug had been previously administered to adults and/or (older) children with minimal adverse reactions, and it was to be administered only once or twice. In four cases, the adverse effects of the drugs to be tested were not regarded as minimal; once, for instance, because of the expected toxicity of a chemotherapeutic drug and once because adult studies had revealed a considerable risk of vomiting. The risks of three other studies were considered to exceed the minimal level due to the study design: two studies involved a risk of overdosing or underdosing painkillers; the third study included simultaneous IV insulin and glucose infusion.

Regarding “minimal burden”, the CCMO mainly looked at the number of invasive procedures and the time-consuming character of a study. Fifteen studies involved a few venipunctures or blood sampling from pre-existing IV cannulas in hospitalised children; this was not considered a problem. Three others involved a 1-day admission to the hospital with an indwelling IV cannula for blood sampling, followed or preceded by one to six short visits that included a venipuncture. These burdens were also considered acceptable. The burdens of nine studies were considered to exceed the minimal level. Eight studies involved more days in hospital (occasionally overnight), more visits and/or more invasive procedures. For the ninth study, admission to the hospital was not required, but the participating children were to undergo a muscle biopsy, several injections and an MRI scan.

In total, 12 studies were considered to involve risks and/or burdens that exceeded the minimal level. In four of these 12 studies, the risks and burdens were considered minimal after the investigators modified the protocol. This was not possible in the eight other cases, all of which being early phase drug studies. Four of these eight studies were definitively rejected, and, as mentioned earlier, in two of these cases, the requirement of minimal risk and burden was the sole reason for rejection. The other four studies were, in first or second instance, approved (table 3). The committee's official reasoning behind one of these four approvals was that, upon further consideration, the study could be considered to provide direct benefit and, hence, did not have to comply with the requirement of minimal risk and burden. In the three other cases, the committee eventually argued that the risks and burdens could be considered minimal after all. In all four cases, the committee meeting minutes suggest that, in light of the importance of the expected results, the committee wanted to avoid rejection.

Table 3

Six early phase drug studies with risks and/or burdens exceeding the minimal level

Discussion

We analysed the approval/rejection decisions of the CCMO in order to evaluate whether the requirement of “minimal risk and burden” for paediatric research without direct benefit compromises the ability to obtain data necessary for improving paediatric care and, hence, should be reconsidered. When it comes to the protection of children participating in research, the requirement of minimal risk and burden plays a fundamental role in both the European Convention on Human Rights and Biomedicine and in the Declaration of Helsinki, which means that the data are of relevance beyond the local situation in the Netherlands.

Our analysis showed that, out of the 165 proposed paediatric studies without direct benefit, 11 were definitively rejected based on this requirement of minimal risk and burden, three of which without any other reason for rejection. Early phase drug studies, essential for developing drugs for children, did relatively often not comply with the requirement: four of the 11 rejected studies were early phase drug studies, and the in-depth analysis revealed that four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal. In these last four cases, the committee apparently felt that the rejections that would be required when using its usual interpretations of the concepts involved would not lead to an optimal balance between the ethical demand to prevent harm to participants and the ethical demand to improve paediatric care by developing new drugs. In order to not have to reject the proposed studies, the committee “stretched” the meaning of the concepts.

One may question whether this means that the requirement of minimal risk and burden should be reconsidered: the concepts of “minimal risk” and “minimal burden” seem vague enough to allow for far more permissive interpretations in case of research that is considered very important. However, we believe that that position is untenable for two reasons. First, the concepts may be vague, but they are not that vague: they clearly exclude procedures such as a muscle biopsy, or the administration of a drug with a yet unknown safety profile. The CCMO managed to assess fairly consistently whether a study involved “minimal risk” and “minimal burden”, and even the committee's standard interpretations of “minimal risk” and “minimal burden” were already rather permissive compared to the definitions provided by the Council of Europe (eg, admission to hospital, insertion of an IV cannula, administration of a drug).4 Second, it is of utmost importance to create more openness around those studies that are approved despite higher levels of risk and burden. Considering the major importance of research in children, such higher levels of risk and burden may be justified in exceptional cases. Yet, when such exceptions are made, this must be done explicitly and the reasons for doing so must be transparent and reviewable. As long as the regulatory framework does not allow for exceptions, this will remain impossible.

At the beginning of 2008, the EU-recommended revision of the current regulatory framework by allowing “a minor increase over minimal risk” for all trials with children that are deemed to result in a benefit for the group of children with the same disease.7 On the basis of our data, three comments can be made on this EU recommendation. First, our data show that “a minor increase over minimal risk” may be insufficient to solve the problem. One exceptionally promising and important study that was approved by the CCMO involved a muscle biopsy, a procedure generally considered to pose even more than a minor increase over minimal risk.7 13 A minor increase in acceptable risk would still have left this proposal unacceptable. Second, on the other hand, for those studies that can be performed with minimal risk and burden, a minor increase in acceptable risk would be too much. We have shown that, when faced with the requirement of minimal risk and burden, in many cases, the objectives of a study could be accomplished with less bothersome procedures. Increasing the acceptable level of risk for all studies with “benefit for the group” would decrease the pressure on the question whether no other viable option exists to obtain the desired results. Third, the CCMO often rejected a proposal because the research burden was considered to exceed the minimal level. This implies that guidance should not focus on risks alone.

Rather than increasing the acceptable level of risk a bit for all studies resulting in benefit for the group, the most promising revision may be to leave the requirement of minimal risk and burden intact, and to allow for exceptions when dealing with exceptionally promising and important research. When allowing such exceptions, it remains of utmost importance to evaluate thoroughly whether the desired results can be obtained with direct benefit or with lower levels of risk and burden, within the proposed design or within a different study design: exposing children to higher levels of risk and burden must always be regarded as a last resort.

What is already known on this subject

  • Some studies necessary for improving paediatric care do not provide the participating children direct benefit, which means that strict limits are required regarding their risks and burdens.

  • In 2008, the EU proposed allowing “a minor increase over minimal risk” for all drug studies without direct benefit. Until that date, the only limit recognised in Europe was “minimal risk and burden”.

  • So far, no empirical data have been published that show whether the requirement of “minimal risk and burden” indeed should be reconsidered.

What this study adds

  • Our data suggest that the requirement of minimal risk and burden should indeed be reconsidered: early phase drug studies often do not comply with it, which may hinder drug development for children. Research Ethics Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution.

  • The EU recommendation does not seem to be the most promising revision: the “minor increase over minimal risk” may sometimes be insufficient and, in other occasions, expose children to unjustified risks.

Acknowledgments

We would like to thank the CCMO for providing full access to all documents required for this analysis and are very grateful for the hospitality and helpfulness of the secretariat members during the months spent at their office. We are also grateful for the helpful comments on earlier drafts of this manuscript by Lynne Ball, Charlene Versluys, Boukje van der Zee and Merijn Bijlsma. In addition, we acknowledge the financial support of The Netherlands Organization for Health Research and Development (grant number 92003475).

References

Footnotes

  • Competing interests None.

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