The moral limits of medical research with children
Westra, A.E.
Citation
Westra, A. E. (2011, June 30). The moral limits of medical research with children. Retrieved from https://hdl.handle.net/1887/17752
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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Note: To cite this publication please use the final published version (if applicable).
ChApter 1
General introduction
Children are ‘the victim of protection-based regulations’, Dutch researchers warned a few years ago in Medisch Contact, the weekly magazine of the Royal Dutch Medical Association.1;2 The researchers complained that their very promising research proposals, intended to explore the safety and optimal dosing schedules of new drugs for children with HIV and brain tumors, had been rejected by the Dutch Central Committee on Research with Human Subjects (CCMO). The CCMO itself in its annual report indicated that because of the strict Dutch Medical Research with Human Subjects Act (WMO), the committee had seen no other option than to reject the proposed studies.3 Under the heading of ‘searching for a new balance’, the CCMO suggested that the WMO might be too strict regarding the upper limits of acceptable risks and burdens in so-called ‘non-therapeutic’
studies, and should be reconsidered.
The question of whether the rules for non-therapeutic research with children should be liberalized, touches upon an interesting ethical dilemma.4 At first sight, the answer may seem evident: when dealing with a sick child, all people concerned want the best treatment to be available, which implies that there should be unrestricted possibilities for doing research into treatments for all kinds of diseases that may occur during childhood. However, the situation is more complex: research participation usually involves some risks and burdens to the research subjects, and children lack the capacity to decide whether they want to bear these risks and burdens. This is particularly problematic in case of non- therapeutic studies, which do not offer the subjects a compensating prospect of direct benefit, which means that the research subjects face the risks and burdens solely for research purposes. Thus, the dilemma is how to facilitate those studies that may improve medical care for children as a group, while adequately protecting the individual research subjects against research risks and burdens.5
This dilemma is neither typically Dutch nor new: in the past century, the dilemma has been acknowledged and addressed worldwide, and as a consequence, the WMO and several other codes and regulations now allow review boards to approve non-therapeutic studies with children only if involving ‘minimal’ risks and burdens.
Yet, the CCMO’s suggestion to reconsider this requirement of minimal risk and burden provides reason to re-examine the ethical underpinnings of this requirement, and to refine, where possible, the ways in which these ethical underpinnings are translated into practice. We acknowledge that the interests of the research subjects should always come first, but hypothesize that less research proposals need to be rejected if the ethical review procedure will be refined. Accordingly, the question that will be addressed in this thesis is: How to facilitate more of those studies that may improve medical care for children as a group, while still adequately protecting the individual research subjects against research risks and burdens?
In this introductory chapter we will provide the necessary background information. We will first explain the two sides of the ethical dilemma: 1) the reasons for conducting medical research studies with children, including
‘non-therapeutic’ studies; and 2) the reasons for protecting research subjects, in particular if these research subjects are children. Then, we describe how the WMO and other relevant ethical codes and regulations have addressed this dilemma, and how this has resulted in the current tension regarding the widely felt need for more research with children. In this chapter, we will furthermore describe the aim, relevance, terminology and outline of the thesis.
THE ETHICAL DILEMMA
Reasons for conducting medical research with children
The main reason why research with children is necessary to improve medical care for children as a group is that novel treatment modalities for children cannot be developed and tested through research with adults, because: 1) certain diseases only occur in childhood; 2) even diseases that occur both in adults and in children, may have other manifestations in children, and thus may require other types of treatment; and 3) for diagnosing diseases in childhood, reference values have to be collected in healthy children in different age groups. Yet, even in case of diseases that have the same manifestations in adults and children, research in adults may be insufficient. In this context, drug studies are of particular concern.
Data from adult drug studies cannot simply be extrapolated to children, because human growth is not a linear process: age-associated changes in body composition and organ function are dynamic and can be discordant during the first decade of life.6 For example, the activity of drug-metabolizing enzymes may be relatively low (or high) during certain phases of childhood, as well as the elimination of the drug by the kidney.6 In addition, age-associated differences have been found in the relation between the blood levels of certain drugs and their efficacy.6 Thus, a drug that has been proven safe and effective in adults may be harmful to children, or children may require relatively low (or high) doses for the drug to be effective.
Reasons for conducting medical research with children:
non-therapeutic studies
Medical research can be distinguished from medical care by being conducted to develop generalizable knowledge, instead of being conducted to benefit an individual patient. However, medical researchers often aim to combine medical research with medical care. In such cases, the researchers conduct their study to develop generalizable knowledge, but at the same time intend to treat (or diagnose, or prevent) the disease of the research subjects. As a consequence, the study can directly benefit the research subjects. In the Netherlands, such studies are usually referred to as ‘therapeutic’ studies.7
Unfortunately, not all necessary data can be obtained within such a therapeutic design. Typical examples of non-therapeutic studies are studies collecting
reference values in healthy children. Other examples are studies that investigate the changes of physical functions in relation to the underlying disease, to better understand the disease (i.e., studies into pathophysiologic mechanisms). Although such studies often form an essential step towards developing a diagnostic test or treatment for a disease, the subjects usually cannot directly benefit from participating in the study.
Studies that are part of the ‘early’ phases of drug development in principle are also categorized as non-therapeutic.7 Drug development studies are commonly classified into four phases: phase I (studies in small groups of patients or healthy subjects, mainly testing safety), phase II (studies in small groups of patients, testing dosing requirements and preliminary efficacy), phase III (randomized controlled trials, testing efficacy in large groups of patients) and phase IV (post marketing surveillance). The group of so-called early phase studies consists of all phase I studies and some of the phase II studies. The two studies that were described in the Medisch Contact articles mentioned before are examples of such early phase studies. Appendix 1 (example studies 1 and 2) provides more information about these exemplary studies.
Reasons for protecting research subjects
So far, we have discussed one side of the ethical dilemma: why research studies with children, including ‘non-therapeutic’ studies, are necessary for improving medical care for children as a group. Below, we will discuss the other side of the dilemma: why research subjects should be protected, in particular if these research subjects are children.
Before discussing the need to protect children, we will first consider the need to protect research subjects who are considered competent to give informed consent (a voluntary and knowledgeable permission to participate in a study).
Some people believe that research with subjects who are competent to give informed consent is not that complex from an ethical point of view. However, for two reasons, we believe it is not that simple. The first reason is that researchers may not always ask for the subjects’ informed consent, if not required to do so by law and/or by ethical review boards. The second reason is that informed consent is important for ethical research, but not sufficient. Studies must also in themselves be ethically acceptable. For example, they must address a relevant question, they must be scientifically valid, and the potential benefits to the subjects and to society must be proportionate to or outweigh the risks and burdens to the subjects.8 The subjects are usually not fully able to judge whether such other requirements are fulfilled, because they lack the required skills and have to rely on the information presented by the researchers. Thus, if not reviewed by review boards, studies could be unethical despite the informed consent of the research subjects.
Unfortunately, a range of case-series indicates that the fear for unethical research with competent subjects is not merely hypothetical. The medical
experiments in Nazi concentration camps, which typically resulted in death or permanent disability, are extraordinary examples.9 Yet, also in less extraordinary situations, ethically questionable studies have been conducted. In 1966, an American professor of anesthesiology described 22 post-World War II examples that illustrate a wide range of dubious research practices, such as withholding effective treatment, knowingly exposing subjects to drugs that cause serious adverse effects, and/or neglecting the informed consent procedure.10 In 1967, also a physician from the United Kingdom published his collection of examples of unethical research.11 A well-known example of later date is the Tuskegee syphilis study, in Tuskegee, which studied the natural progression of untreated syphilis in 400 impoverished black men between 1932 and 1972, despite the fact that penicillin was validated as an effective cure for the disease in 1940.12
Apparently, even after World War II, researchers occasionally attached more importance to scientific considerations (or to financial considerations, or to their career) than to protecting their research subjects, or perhaps they were just not always aware of the fact that there might be something ethically ‘wrong’ with their research plans. The important lesson was that if one aims to avoid exploitation of research subjects, having all proposals for research with human subjects reviewed by independent ethical review boards is vital, even if these subjects are competent to give informed consent. The review procedure ensures that the researchers set up proper informed consent procedures and also ensures that people are approached with the option of entering the study only when agreeing to do so would be a reasonable choice.13
Reasons for protecting research subjects: children
The main reason for children requiring additional protection in research is that they are deemed unable to give informed consent, because of their limited ability to promote and act upon their own interests. Parents can give consent on behalf of their children, but such a proxy consent can never fully replace the truly personal consent one would aim for in a research setting.14 One could argue that this does not matter, because parents have the authority to make decisions on behalf of their children just as adults have the authority to make decisions for themselves (parents can make many decisions for their children free of state intervention, and why should this not be one of them?).15 However, the decision to enroll a child in research is not just a regular family decision: researchers and society are also involved, and the risks and burdens can be substantial.16
Of particular concern are the non-therapeutic studies. In 1970, moral theologian prof. P. Ramsey drew the attention to this problem.17 Ramsey did not deny that parents have the moral authority to give proxy consent on behalf of their children, but he argued that their moral authority is limited in case of non- therapeutic research because ‘no parent is morally competent to consent that his child shall be submitted to hazardous or other experiments having no diagnostic
or therapeutic significance for the child himself’.17 The problem, according to Ramsey, is that ‘to attempt to consent for a child to be made an experimental subject is to treat a child as not a child. It is to treat him as if he were an adult person who has consented to become a joint adventurer.’17 It is also to treat him as a means only, which violates the Kantian principle of respect for persons.17
THE ETHICAL CODES AND REGULATIONS
In response to the growing awareness that research subjects need to be protected, over the years, several national and international ethical codes and regulations on human subject research have been developed. Most of these codes and regulations explicitly mention one or more specific requirements for non-therapeutic studies with children. Generally, these requirements are:
1. The risks and burdens should not exceed an upper limit of acceptable risks and burdens (generally, this upper limit is ‘minimal’)
2. The risks and burdens should be minimized (i.e., should be as low as possible) 3. The study should be ‘group-related’ (i.e., could not be performed with com-
petent persons)
4. The study should be ‘group-directed’ (i.e., should aim to benefit the group to which the subjects belong)
Of course, to be acceptable, non-therapeutic studies with children should also meet the general requirements for ethical research (e.g., they must address a relevant question and must be scientifically valid), and the modified informed consent requirements for research with children (i.e., consent of the legally authorized representative; in addition, ‘assent’ of those children able to give such permission).
Regarding the first criterion, which is the requirement of minimal risk and burden, two observations deserve attention. First, this requirement of minimal risk and burden is the only factor potentially compromising the ability to obtain the data that are necessary for improving medical care for children as a group.
The requirement of group-relatedness may also hinder non-therapeutic research with children but does not compromise the ability to obtain the required data:
if studies that cannot fulfill the requirement of group relatedness, the data apparently can be obtained using adult studies. Second, this requirement is in two ways absolute: 1) it is meant to provide an absolute threshold; regardless of the importance of the proposed study; and 2) exceptions are not allowed.
In this paragraph, we will provide an overview of those ethical codes and regulations that are legally binding in the Netherlands and/or are morally authoritative, and will also briefly describe the approach that was taken in the United States (US). Table 1 provides a systematic overview of how these various codes and regulations address the above-mentioned ethical requirements. It shows
that, although none of the codes and regulations uses the same terminology, most of them are fairly similar in outcome. Exceptions are the US Federal Regulations, which allow for exceptions to the requirement of minimal risk and burden, and the European Clinical Trials Directive, which does not distinguish between therapeutic and non-therapeutic research.18;19
The first ethical codes and regulations
The first internationally acknowledged set of research ethics principles for human experimentation was laid down in the Nuremberg Code after the Nuremberg Trials at the end of World War II.20 This code explicitly focuses on the informed consent of the subjects (the first sentence of the code states that ‘The voluntary consent of the human subject is absolutely essential’), which implies that research with children is prohibited.20 Article 7 of the 1966 United Nations’ International Covenant on Civil and Political Rights, which has been ratified by the Netherlands, includes a similar statement.21 It has, however, been argued that there is no reason to assume that the aim of Article 7 of this international covenant is to completely rule out non-therapeutic research with children.22;23
The World Medical Organization in its 1964 Declaration of Helsinki also focused on informed consent but did already explicitly allow therapeutic research with incompetent persons.24 After several revisions this declaration currently also allows, under strict conditions, what it used to call non-therapeutic research.
Article 27 states, regarding incompetent subjects: ‘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 minimal burden.’25
The Netherlands
The Dutch Medical Research with Human Subjects Act (WMO), is of fairly recent date: it came into force in 1999.4 This is not to say that before that time, the ethical aspects of research with human subjects were neglected in the Netherlands: the first review board was already established in 1965, and an influential doctoral dissertation on this topic was published in 1985.26;27 There also has been a long time span between the first advice on this issue and the approval of the final version of the WMO.28
The main reason for the long time span between the first draft of the WMO and the eventual approval of the final version was the controversy regarding non- therapeutic research with children and other incompetent subjects. In the first draft of the WMO, non-therapeutic research with children and other incompetent subjects was permitted, but several political parties disagreed with this proposal and advocated a complete ban on such research. The Christian Democratic Party, for example, argued that the fact that such a ban would hinder science, would not
Four requirements for non-therapeutic research with children, as addressed by several codes and regulations. Name of code or regulation
term for non- therapeutic researchrisk and burden: Upper limitrisk and burden: Minimizationthe requirement of ‘group-relatedness’the requirement of ‘group-directedness’ Declaration of Helsinki, 6th revision (Art. 27)
Research studies without the likelihood of benefit for the subjects.
Minimal risk and minimal burden.Not addressed.The research cannot instead be performed with competent persons.
The research must be intended to promote the health of the population represented by the subject.
WMO (Art. 4)
Research that cannot benefit the subjects.
Negligible risk and minimal drawbacks.All human subjects research (Article 3b): The desired data could not be obtained in a less invasive way.
The research could not take place without the participation of subjects from the category to which the subject belongs.
Not addressed. European
Convention (Art. 17)
Research without the potential to produce results of direct benefit to the health of the person concerned.
Minimal risk and minimal burden.Not addressed.(All research involving children): Research of comparable effectiveness cannot be carried out on subjects who are able to consent.
.. benefit (to the person concerned or) to other persons in the same age category or afflicted with the same disease or disorder or having the same condition. European Clinical Trials Directive (Art. 4)
No such distinction is being made.
No upper limit is mentioned. According to a supplementary document: a minor increase over minimal risk.
The clinical trial has been designed to minimize pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage.
The research should either relate directly to a clinical condition from which the minor concerned suffers or be of such a nature that it can only be carried out on minors.
Some direct benefit for the group of patients is obtained from the clinical trial. US Federal Regulations (Subparts A and D)
Research without the prospect of direct benefit.
Minimal risk. Depending on, amongst others, the importance of the research, minor increases over minimal risk, or even greater increases over minimal risk, are also allowed.
(All human subjects research): Risks to subjects are minimized: By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
Not addressed.Not mentioned in relation to non- therapeutic r
esearch involving minimal risk.
provide sufficient argumentation to allow non-therapeutic research with children.
However, prof. H. K. A. Visser, at that time professor of pediatrics at the Sophia’s Children Hospital in Rotterdam, recognized the consequences of the proposed ban for future sick children. He mobilized his colleagues and as a result, the Royal Dutch Medical Association was asked to send a report explaining the medical profession’s point of view.29;30
A key role in this history was played by a multidisciplinary governmental committee, which was established to solve the controversy, and which is best known by the name of its chairman: prof. L. C. M. Meijers. This committee acknowledged the delicate balance that has to be met between the importance of research and the protection of individual subjects.22 The committee in its report provided an overview of all relevant ethical principles and international law aspects, clarified the confusing terminology, and convincingly showed on the basis of several examples, that non-therapeutic research is indispensable to improve medical care for children as a group. The committee eventually recommended prohibiting non-therapeutic research with children and other incompetent subjects unless: 1) the study involves only ‘minimal’ risks and burdens; 2) the study is group-related;
and 3) during the study, expressions of objection of the subjects are respected.22 On the basis of this report, the WMO-paragraph concerning research with minors and others unable to consent was adjusted. The final version of the WMO was accepted by the Parliament in 1997 (See Appendix 2). According to the evaluation of the WMO in 2004, the law functions well for all parties involved; the main suggestion for improvement being more clarity regarding its scope.31
Europe: currently, no clear consensus
The relevant European documents are the Council of Europe’s European Convention on Human Rights and Biomedicine (European Convention, 1997) and its Additional Protocol (2005), the Clinical Trials Directive (2001), and a document that provides guidance on the application of this Clinical Trials Directive to trials with children (2008).19;32-34 The European Convention is not binding in the Netherlands, as it has been signed but not yet ratified. Until recently, however, this document could be regarded as expressing the European consensus on the acceptability of medical research with human subjects. Article 17 of the European Convention states, that non-therapeutic research with children may only be approved if involving minimal risks and burdens.32
The Clinical Trials Directive, on the other hand, is legally binding (albeit only in relation to drug research and not to other types of research) and has been implemented in the WMO (See Appendix 2, Article 13e, for the added passage that concerns drug research with children). Contrary to the ethical codes and regulations mentioned before, this Clinical Trials Directive does not distinguish between therapeutic and non-therapeutic research with children, and (thus) does not provide limits regarding the acceptable levels of risk and burden in
non-therapeutic research. However, such limits can be found in a supplementary document explaining how to apply the Directive to studies with children.34 This document still allows more research than the WMO and the European Convention, as it states that ‘a minor increase over minimal risk’ can be regarded as acceptable.
US: more possibilities for approving non-therapeutic studies
In the US, in 1974, the US National Commission for Protection of Human Subjects (US National Commission) was charged with the task of recommending regulations that would protect the rights of human research subjects. When this commission approached the topic of children as research subjects, it decided to initiate its study with a debate. To do so, the commission invited Ramsey (the moral theologian mentioned before, who had argued against non-therapeutic research with children) as well as an opponent of Ramsey’s point of view: prof. R.
P. McCormick. McCormick countered Ramsey’s argument by drawing attention to the child as a participant in a social reality, rather than as an isolated and vulnerable entity.35 The US National Commission’s eventual report went for a good part with McCormick and defines levels of risk and associates those levels with the prospect of direct benefit and with the importance of the research.36 Research that does not offer the subjects a prospect of direct benefit should in principle not involve more than ‘minimal risk’; however, if important (and if fulfilling several additional criteria) they may also involve ‘a minor increase over minimal risk’, or even higher levels of risk. In the eventual US Federal Regulations’, these recommendations can be found in the subpart on research with children.18
THE NEED FOR MORE RESEARCH
Although most of the ethical codes and regulations currently allow for non- therapeutic studies in children, this is, as we have shown, only under strict conditions; the most restricting condition being the requirement of minimal risk and burden. With this protection of individual research subjects came a drawback:
diseases that may occur during childhood are insufficiently studied. Of particular concern is the fact that many of the drugs that are currently used to treat children are either not licensed for use in children or are prescribed outside the terms of their product license (off-label prescribing). This problem is present in all age groups and in all levels of care, the group most seriously affected being children in neonatal intensive care units.37-44 The risk of prescribing off-label and unlicensed drugs in children is not yet fully clear; however, it can be expected that such use involves a greater risk of adverse effects.45 One could say, that children have become so-called ‘therapeutic orphans’.46 Currently, the need for more research in children is a matter of consensus on a global scale.
The requirement of minimal risk and burden for non-therapeutic studies is definitely not the only reason for the lack of research, in particular not in case of
drug research. Because of the small numbers of children with certain diseases, and because of the need to study children of different ages, research with children is also practically difficult and commercially less interesting than drug research for adults.47 However, in response to the growing awareness of the need for more research in children, most of these problems by now have been addressed.
In response to the practical problems, in several fields, research groups have started cooperating with each other. Furthermore, researchers have developed methodologies and techniques that may decrease research risks and burdens.
An example is a statistical technique that is known as non-linear mixed effects modeling.48 Using this technique in early phase drug studies may significantly decrease the number of blood samples required per child.
In response to the financial problem, both the US and Europe have decided to use financial incentives to encourage the pharmaceutical industry to test potential drugs for use in children. In Europe, the Pediatric Regulation became effective in January 2007.49 This regulation offers patent protection to pharmaceutical companies that test their medications in children and also provides for a European committee to oversee and assess researchers’ plans for developing medicines for children. In the US, the approach is of earlier date, and is twofold. First, there is the ‘pediatric exclusivity provision’ in the Food and Drug Administration Modernization Act (renewed in 2002 as the Best Pharmaceuticals for Children Act), which just as the European Pediatric Regulation offers patent protection.50 Second, there is the Pediatric Research Equity, which requires pharmaceutical companies to test their products in children.51 These measures have been described as ‘a carrot and a stick’: the patent protection being the carrot; the testing requirements being the stick.47 Both of these incentives were renewed in 2007 and are now in effect until October 2012.16
Whereas the practical and financial problems now for a great part have been tackled, the ethical restriction on non-therapeutic research has remained unaddressed. As previously mentioned, we believe that the interests of individual research subjects should always prevail. However, considering the growing awareness of the need for more research, it may be helpful to re-examine and refine the way in which these individual research subjects are protected.
THIS THESIS
Aim
The Dutch law and several other ethical codes and regulations forbid review boards to approve non-therapeutic studies with children when involving more than
‘minimal’ risks and burdens. It has been suggested to liberalize this restriction, in order to enable researchers to conduct more of the studies that are necessary for improving medical care for future sick children. However, this restriction on non- therapeutic research with children was established for a good reason: it ensures
that individual children will not be exposed to (relatively) high levels of risk and burden solely for research purposes. Therefore, in this thesis, we aim to examine the following question: ‘How to facilitate more of those studies that may improve medical care for children as a group, while still adequately protecting individual research subjects against research risks and burdens?’
We aim to do so by first investigating how the requirement of minimal risk and burden for non-therapeutic research with children currently functions in practice, followed by a problem-based re-examination of the ethical underpinnings of this restriction. Where possible, we will recommend how to refine the ways in which these ethical underpinnings are translated into practice. We hypothesize that when refining the ethical review procedure, aiming for ‘tailor-made protection’, less research proposals need to be rejected.
Relevance
Despite all the developments in this field, hardly any research on the ethical aspects of research with children has been carried out in the Netherlands since the work of the Meijers Committee in 1995.22 Several foreign ethicists have published on this topic, but most of them have focused on possible interpretations of the relevant parts of the US Federal Regulations. Although these analyses may serve as an important source of how matters are dealt with in the US, we cannot apply them directly to the situation in the Netherlands. Recently, a Dutch expert committee (named after its chairman prof. J. E. Doek) has addressed the CCMO’s word of warning (upon request of the Dutch the Minister of Justice and the State Secretary of Health, Welfare and Sport); yet, this committee seems to have focused fairly narrowly on the need for more research.52 We recognize the need for more research in children, but also acknowledge the complexity of the ethical dilemma. Thus, we will explore in this thesis how to facilitate more research, but we will do so from an ethical perspective, within a multidisciplinary study group, aiming to improve rather than to compromise the protection of individual research subjects. Considering the fact that the requirement of minimal risk and burden plays a fundamental role in both the Declaration of Helsinki and the European Convention, our recommendations will also be of relevance beyond the national situation in the Netherlands.
Terminology
The terminology used to refer to the concepts at stake, and/or the exact meanings attached to these terms, is not always the same. Therefore, we will explain in this paragraph the choices we have made regarding the terminology used in this thesis.
For example, the terminology used in the WMO partly differs from the terminology that is used in the Dutch moral debate and from the terminology that is used in the international codes and regulations.53 The most relevant differences are the following: 1) ‘negligible risk’ (WMO) versus ‘minimal risk’ (Dutch moral debate
and international codes and regulations); 2) ‘minimal drawbacks’ (WMO) versus
‘minimal burden’ (Dutch moral debate and international codes and regulations), and 3) ‘research that cannot (directly) benefit the subjects’ (WMO and international codes and regulations) versus ‘non-therapeutic research’ (Dutch moral debate).53 We have chosen to use the terms that are used in the Dutch moral debate in this introductory chapter as well as in the general discussion. Thus, in these chapters we speak of ‘minimal risk’, of ‘minimal burden’ and of ‘non-therapeutic research’.
In the other chapters, (to be) published in international journals, we have chosen to adjust to the international moral debate. This means that in these chapters we do not speak of ‘non-therapeutic research’ but of ‘research that cannot directly benefit the subjects’ (or, of: ‘research without direct benefit’).
We will also explain our use of five concepts that will play an important role in this thesis. First, by ‘children’ we mean all persons who have not yet attained the legal age for providing informed consent for participation in a research study.
In the Netherlands, this means all persons who are younger than 18 years old.
Second, by research ‘subject’ we mean someone who takes part in a research study. We have chosen in this thesis not to use the term ‘participant’ (except in Chapters 2 and 7) because this term suggests an active role, whereas young children’s contributions usually are rather passive: they do not fully understand the project to which they are contributing and do sometimes not even know that they are a research subject. Third, by research (or study) ‘procedures’ we mean all tests and interventions that can be part of a medical research study. Procedures can be classified in various ways, for example as being either invasive (e.g., blood draws, biopsies and the injection of a drug) or non-invasive (e.g., questionnaires and visits to hospital), or as being either experimental (e.g., the injection of a drug that has not yet been sufficiently tested), or accepted medical procedures (e.g., blood draws, biopsies, questionnaires and visits to hospital).23 Fourth, by (ethical) ‘review boards’ we mean committees reviewing the ethical acceptability of research proposals. In the UK, review boards are called Research Ethics Committees (RECs); in the US they are called Institutional Review Boards (IRBs).
In the Netherlands review boards are called Medical Ethical Review Committees (METCs); the CCMO oversees the activities of the METCs and reviews specific protocols. Fifth, by ‘direct benefits’ we mean medical benefits resulting directly from an (experimental) research procedure. Direct benefits should on the one hand be distinguished from non-medical benefits such as financial compensation, and on the other hand from the eventual benefits to society (i.e., to future patients).
OUTLINE
After this introductory chapter, Chapter 2 will report on an analysis of the relevant approval/rejection decisions made by the CCMO. During this project, we have examined the nature of the main issue, i.e., to what extent does the requirement of minimal risk and burden compromise the ability to obtain data that are necessary for improving medical care for children as a group? This analysis also revealed to us that this restriction on non-therapeutic research with children in fact poses two additional ethical issues. The first is that it is not always clear whether a study should be regarded as a non-therapeutic study, and thus should fulfill the requirement of minimal risk and burden. The second is that without clear definitions of ‘minimal risk’ and ‘minimal burden’, the requirement of minimal risk and burden may not provide a reliable level of protection.
Chapters 3 to 6 address these two related issues. Chapter 3 analyzes the ethical underpinnings of the distinction between non-therapeutic and therapeutic studies and then explores whether distinguishing between non-therapeutic and therapeutic procedures may be more helpful. Chapter 4 provides an overview of the problems posed by the US definition of ‘minimal risk’ and then defends alternative definitions of ‘minimal risk’ and ‘minimal burden’. Chapter 5 and 6 describe two empirical studies that we conducted to provide more insight into the meaning of the concept of ‘minimal burden’.
Chapters 7 and 8, then, address the issue that some data that are necessary for improving medical care for children as a group cannot be obtained with minimal risks and burdens for the individual subjects. Chapter 7 considers the European codes and regulations at stake: some Dutch researchers suggested that the Netherlands should ‘follow Europe’, but what exactly would that mean?2 Chapter 8 analyzes whether it would be a sensible idea to follow the US Federal Regulations, which in certain circumstances allow for exceptions to the requirement of minimal risk and burden. To do so, we first explore the ethical grounds for accepting only minimal risks and burdens and conclude from there which factors are relevant when considering allowing exceptions to this requirement.
Finally, in Chapter 9 the findings of this thesis are summarized in relation to the three issues that we found to be related to the requirement of minimal risk and burden for non-therapeutic research with children. We will provide recommendations on how to solve the three issues and improve the ethical review procedure, we will discuss alternative solutions, and we will provide suggestions for further research. Furthermore, we will in this chapter suggest which parts of the WMO we think should be modified to make the implementation of our recommendations possible in the Netherlands, and we will explore the implications of our recommendations.
