TREAT-NMD Tutorials

by Pauline McCormack and Simon Woods
PEALS, Newcastle University

This tutorial aims to introduce the main ethical issues in relation to children’s participation in clinical trials.

Learning Outcomes

At the end of this tutorial you should:

• Be able to recognise some fundamental ethical principles
• Be able to identify the basic arguments for carrying out research on children
• Be conversant with the discussion around reasons for including children in research
• Have a working knowledge of the application of the Declaration of Helsinki in relation to children’s research
• Be familiar with the ethical issues related to research on children with chronic illness

Contents

• Aims and outcomes
• What is ethics?
• Children in clinical trials – introduction
• Article – ‘Ethical concerns regarding guidelines for the conduct of clinical research on children’
• Children in clinical trials – discussion
• Rare disease and Duchenne muscular dystrophy
• Introduction to ‘The World Medical Association (WMA) Declaration of Helsinki Ethical
• Principles for Medical Research Involving Human Subjects’
• The Declaration of Helsinki
• Clinical trials for children with rare diseases – empirical issues
• Article – ‘Ethical issues of clinical trials in children: a European perspective’
• Conclusions
• Further reading

Copyright: This tutorial is the copyright of Newcastle University and may not be reproduced or copied elsewhere. It is freely available for non-profit educational use.

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Take a few moments to think about and write down words and ideas you associate with the term “ethics”

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You may have listed things such as:

• learning how to behave in society
• codes of practice
• your personal morality
• professional behaviour
• deciding between right and wrong
• having religious beliefs
• following the law

Ethics is moral philosophy. Ethics is the study of the theories of good and bad, right and wrong. More specifically it involves the critical evaluation of moral arguments about the interests and welfare of morally significant beings. The term “beings” can be taken to include people, animals, living things in general or even the whole world as a living environment. In the context of medical ethics, the topic of interest here, the emphasis is upon human beings, their welfare and interests.

A human being is seen as morally signficant if they have an affect on the world around them or the lives of others.

Ethics and morals

In common language morals and ethics are often distinguished. Morals and morality are seen as concerning the standards of personal behaviour, the sorts of things tolerated or not within a society. Ethics is often regarded as something distinct, a rather technical study of values. In philosophy the two are not distinguished in this way; so ethics and morals can be used interchangeably. In this tutorial we will generally use the term “ethics”.

Decisions which guide action

Ethics is not just about theories but also about making judgments about the right course of action. In other words, engaging in ethics as an activity, involves formulating action-guiding decisions, giving the best possible reasons for acting in one way rather than another. In this section we are concerned with medical ethics more broadly and research ethics specifically. In both cases the ethics we are interested in is not the highly theoretical ethics of the philosopher but a more pragmatic form of ethics concerned with the rights and interests of the patient/research subject, and the duties and the responsibilities of the researcher/clinician as well as the wider societal interests in health-care and research.

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All people expect to receive the best possible treatment and care when they are sick and this expectation can only be met when there is robust evidence, research evidence underpinning their care and treatment. Many patients benefit because others before them have been prepared to take part in clinical trials. It is widely acknowledged that being a research subject in a clinical trial is different from being a patient.

A patient can expect to receive treatment designed to directly benefit them, from doctors who have a duty of care towards them. The design and methods of a clinical trial aim to produce generalisable knowledge and not to provide treatment which is directly in the interests of the research subject.

Treatment		Trial
Treatment is individual		Development of a new drug is communal
Primary aim is to benefit the patient		Primary aim is to generate data
Can adjust therapies to the individual		Any adjustment is limited by trial protocol

So the ethical considerations in research differ in significant ways from the ethics governing clinical care.

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It is often argued that ethical research should be highly risk averse, seeking always to expose the least vulnerable to the lowest burden of risk. As a consequence the ethical hurdle is raised according to the vulnerability of the research subject.

Vulnerability

To be vulnerable means literally to be open to harm due either to intrinsic factors for an individual or due to extrinsic factors associated with the environment or context in which the person is placed. Children have often been regarded as inherently vulnerable. Furthermore many children are unable to consent for themselves and some people see this as weakening an important safeguard.

So in evaluating the ethical issues associated with including children in research there are several things to consider:

• the case for the inclusion of children
• the burden of risk they are exposed to
• the potential benefit which may come from the research and who will be the recipient of such benefit
• the mechanisms by which the interests of children are safe-guarded, such as the process of consent and the right to withdraw

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Activity >
Read the following article and make notes on the questions below

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Ethical concerns regarding the guidelines for the conduct of clinical research on children.
S.D Edwards, M.J. McNamee J Med Ethics 2005 31.351-354

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1. The authors list three reasons why research on children is justified. List these reasons. Can you think of any others? To balance the case, what concerns about including children in research might there be?
2. The authors offer a particular interpretation of one of the priorities of the Declaration of Helsinki and they link this to Kant’s imperative. First, put Kant’s imperative into your own words. Do you agree with the authors’ interpretation? Give your reasons why you agree or disagree.
3. The authors claim that children should only be included in research when it is directly in their interests. How do you interpret this claim and do you agree with it?

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Question one

Edwards and McNamee identify the following three factors which go some way to justifying research involving children:

1. Some diseases are exclusively diseases of children and therefore it would be impossible to use subjects other than children for research related to these conditions.
2. Children are not miniature adults and therefore there are real metabolic differences between adults and children.  This means that therapies developed through research using adults cannot always be transferred safely to children.
3. Research with children is necessary in order to understand the normal baseline for children.  It is only possible to understand abnormal reactions to drugs and therapies if the normal range has been established.

Other considerations might include:

• There is a need to build up a body of expertise in research on children so that research will be well managed and safe
• Children with serious conditions will be further disadvantaged if research into children’s diseases is not conducted
• There are many instances of research where it is both of direct benefit to research participants and extremely safe to involve children

There are of course many serious concerns about using children as research subjects these include:

• Young children are unable to consent for themselves and may be unable to understand what is happening to them
• Children may be more easily coerced into co-operating with research than adults
• Children may be more vulnerable to long term side effects from research compounds and procedures

Question two

Kant’s imperative can be expressed in a number of ways but essentially he claims that it is always wrong to use another person as an instrument or tool to achieve a purpose that is not of that person’s choosing.

Reasons to agree
This interpretation of Kant’s imperative does seem to echo the concern behind the Declaration of Helsinki that the interests of the person should always be above the interests of science and society. There is an agreement that it would be wrong to use a person, particularly a person in a vulnerable position, as a “thing” or an “object” to achieve benefits for others. It could be argued that the moral concern expressed here is similar to the arguments used to condemn slavery.

Reasons to disagree
There are several points to observe about the argument being made here. The first is that, although the Declaration of Helsinki is an important instrument, it was inspired by a certain point in time and a certain set of particularly horrific circumstances, namely, the medical research atrocities of World War II. It could be argued that the lessons from that time have been learned, and are reflected at many levels, particularly in the laws and regulations governing research, and in the ethical standards used to educate health professionals. We therefore do not need such a rigid statement because the world has learned from the lessons of the past.

A second consideration relies on two points. The first is that it is not obvious that using another person as an instrument is always and everywhere wrong. For example many people recognise the importance of having a capable military force in which soldiers will carry out orders and not follow their own interests at times of national crisis. Moreover it may sometimes be necessary to enforce conscription as a way of maintaining such a force. These points imply that there is at least one situation when it does seem justified to use people instrumentally.

The second requires the deconstruction of the term “interests”. As an individual I have my own interests, the things I need but also the things I value and consider important. Some interests may be personal and some more general. So although I value the good things in my life like my job, my home, the food on my table, these are also opportunities and resources I would like others to enjoy. It is very likely that I could not enjoy these things unless they were in principle available for everyone to enjoy. In society we work together to make such opportunities and resources widely available, and so there is a common good or interest in which we all share. In the context of medicine and healthcare, the interests of science and society are also my interests. It should also be noted that people are often very willing to pursue important societal interests even in circumstances when they are unlikely to benefit personally. So patients do volunteer to take part in clincal trials that they will not benefit directly from in order to contribute to a common good or interest.

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Question three

This discussion point leads on from the previous one. One interpretation might be that, for something to be in someone’s “direct interests” means either it is something they immediately need and is likely to lead to a direct benefit to them, or it is something that they want and have chosen for themselves because it is something that they value. In the context of children participating in research these conditions might be difficult to meet. One reason is that the research may not deliver the thing that they immediately need. Another is that the child may not be able to choose for him or herself because they are too young or too sick to understand or because they are incapable of giving consent. In most instances research begins from a position of uncertainty or ignorance so it cannot be known if there will be direct benefit to the child or not.

It is possible to regard research as a general good and therefore something worthwhile to participate in as a contribution to a common good. A common good is a benefit in which we all take part. However we would still be left with the dilemma as to whether it would be ethical to include a child in research irrespective of whether they understood this claim about a common good.

If the restrictions argued for in the paper are justified then it may lead to the conclusion that there are just some research questions that cannot be addressed in children. This may in turn imply that some children must live with their health problem because it would be a greater wrong to expose them to research that offers no direct benefit.

An alternative view is to apply the argument about common interests developed in the previous discussion point. However in the context of children one might argue that the relevant “society” is not society in its broadest sense but the society of children with a similar condition. So here one could argue that it would be justified to include children in research where they might not benefit as long as risk to them was minimal and the group of children with a similar condition are likely to benefit.

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There is no single definition of rare disease. Diseases which are rare in some countries may be common in others. In Europe a disease is defined as rare when it affects less than 1 in 2,000 citizens and in the USA less than 1 in 1,500. There are thought to be around 5,000 to 7,000 different types of rare disease which together affect between 6-8% of the population. In Europe this is about 30 million people.

Rare diseases are often:

• chronic, progressive, degenerative, and life-threatening
• disabling: the quality of life of patients is often compromised by the lack or loss of autonomy and the burden on patients and their families can be high
• without an existing, effective cure

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75% of rare diseases affect children
30% of rare disease patients die before the age of 5
80% of rare diseases are genetic

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Rare disease patients face common problems:

• lack of access to correct diagnosis
• delay in diagnosis
• lack of quality information on the disease
• lack of scientific knowledge of the disease
• heavy social consequences for patients
• lack of appropriate quality healthcare
• inequities and difficulties in access to treatment and care

The case of Duchenne muscular dystrophy (DMD)

For the purposes of this tutorial we will use the example of DMD which is a rare disease but also one of the most common genetic disorders affecting children and young adults. DMD usually affects boys and there are approximately 26,000 people in the world with this disorder.

DMD is a severe, muscle wasting condition with onset in early childhood. The progressive muscle weakness and wasting leads to those affected becoming wheelchair bound by their early teens and increasingly dependent on care as they get older. There is no cure. DMD generally leads to death by the early twenties, although in some countries men are living longer. The social and emotional costs and burden for patients and their families are very high.

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Activity >
Watch the following videos

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BrainPOP animation about Duchenne Muscular Dystrophy (4:14)

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Living with Muscular dystrophy (5:37)

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The World Medical Association (WMA) Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects.

The Declaration of Helsinki was first published by the WMA in 1964. It provides international, ethical guidelines for all those involved in conducting medical research. The WMA has no actual powers and the Declaration of Helsinki is not legally binding. In reality, the WMA is seen as authoritative in that it represents the considered opinion of many medical experts from every region of the world and the Declaration carries great weight internationally.

Versions

You need to note that there are different versions of the Declaration of Helsinki. It was first ratified in 1964 and has been amended a number of times since then. The amendment dates can be found at the top of the web version of the Declaration here.

Be aware that the article by Edwards was written in 2005 and will therefore have used a version of the Declaration which is older than the current one.

 

Activity >
Read the Declaration of Helsinki now

 

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World medical association declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

World medical association

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Activity >
Read

Return to the Edwards & MacNamee (2005) article you read earlier.
Re-read the first paragraph under ‘The Importance Of Clinical Research On, With And For Children’.

Can you relate Edward’s three reasons to research on children with rare diseases?

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Ethical concerns regarding the guidelines for the conduct of clinical research on children.
S.D Edwards, M.J. McNamee J Med Ethics 2005 31.351-354

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It is possible to extrapolate Edwards’ three reasons for carrying out research on children, to carrying out research on children with rare diseases thus:

• research into rare childhood diseases needs to be carried out on children with rare disease
• drugs which are to be used on children with rare disease should be tested on children with that disease
• research on children with rare disease is necessary in order to map their normal development and this will inform the appropriateness of clinical treatments

 

Activity >
Now look again at the Declaration of Helsinki

 

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World medical association declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects
World medical association

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Which parts of Helsinki support the three points above?

Could any sections be used to argue against the three points or contradict points you’ve made in your own notes for this tutorial?

Here are some of the sections of the Declaration of Helsinki that could be seen as supporting the three points, you may have noted more:

5 …Populations that are underrepresented in medical research should be provided appropriate access to participation in research.

8. In medical practice and in medical research, most interventions involve risks and burdens.

17. Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood that this population or community stands to benefit from the results of the research.

27. For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorized 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 minimal burden.

All these paragraphs could be interpreted as confirming Edwards’ three reasons. Together they could be summarised as saying, all research involves risk and burdens but it can be carried out on individuals, including those who lack competence, if the community with that disease will benefit.

Here are some of the sections of the Declaration of Helsinki that you could use to argue against the three points, you may have noted more:

9. …Some research populations are particularly vulnerable and need special protection. These include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or undue influence.

21. Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.

It might be argued that these points could be used to disagree with the discussion above. Point 9 could be used to make the case that all children are vulnerable and open to coercion and should not therefore, be included in clinical trials. Point 22 emphasises the need to assess the risk for the individual rather than concentrating on the community which might benefit. Lots of ethical guidelines are open to interpretation like this. Practical ethics is very much based on the day-to-day application of theories and guidelines, at the same time taking into account the personal circumstances of the child concerned, their medical history and needs and the views of their family.

Children diagnosed with DMD are disadvantaged in several ways, by the rarity of their condition, its life-limiting nature and from the lack of effective therapies. The need for research is therefore paramount and can be seen as being in the best interests of the children concerned. The potential benefits of the research outcomes, in terms of improving, extending or saving life, could be seen to outweigh the risks to the individual concerned. It could be argued that children with rare disease and their families have more of a duty to participate in research than children without disease.

On the other hand, children with rare disease should be afforded the same protection from risk and harm that all other children have. The best interests of children with a chronic, fatal disease may not be the same as children who are not ill. We should pay attention to how those best interests are assessed in relation to the child with a rare disease. There should not be an increased expectation for these children to take part in clinical trials simply because they are ill or because there may be benefit to them. To do so would exert an unfair moral pressure to participate.

It is therefore necessary to make a realistic assessment of the risks involved in conducting research but to also consider the benefits and weigh the risks of being too cautious with regard to research. The protection afforded to children with DMD needs to be balanced against the disadvantage of delaying research leading to effective treatment thus potentially harming by omission.

The indirect benefits of trial participation should also be considered since patients say that the altruism of participating in a trial, making a contribution to the fight against the disease, along with the feelings of self-worth and value this brings, is a major benefit in itself.

Activity >
Watch and make notes

The clip below shows part of a workshop about the ethical issues of clinical trials in neuromuscular disorders. The speaker is Dr Simon Woods a bioethicist with PEALS (Policy Ethics and Life Sciences) Research Centre at Newcastle University in the UK. He sets out some of the challenges involved in research using children as research participants.

Watch the clip and in your own words set out the key issues identified by the speaker. Are there any other issues you consider to be important which have not been identified by the speaker?

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The speaker outlines that informed consent and engaging children in research as participants, rather than subjects are important issues. The speaker believes there should be some expectation for children to take part in trials but that, at the same time, their interests need to be protected and this is a fine balance.

The speaker says that parents are obviously key decision makers but that others in society have a role in protecting the interests of vulnerable children.

Traditional approaches to research ethics as reflected in the Declaration of Helsinki have endorsed strongly the principle that the interests of the research participant take precedence over the interests of science and society. The traditional view also regards children as particularly vulnerable. Recognition of this vulnerability is translated into the view that children should only be entered into therapeutic studies where the benefit outweighs the risk, or non-therapeutic studies where there is no or negligible risk.

Activity >
Watch and make notes

Watch the film clip and make notes about the questions below:

• What does the first speaker say about professional roles?
• What main points does the second speaker make?
• Are you convinced by this argument? Give your reasons for or against.

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One of the ethical challenges for the clinician researcher is managing the shift in role between acting as a clinician to a patient, with a focus upon the best interests of that patient, to that of acting as a researcher with the same patient as a research participant. The facilitator suggests that there is the potential for a conflict of interests between these two roles.

You should have identified that the second speaker does not consider that there is a dilemma for the clinician researcher if he/she believes that:

• there is no known better treatment
• that the treatment will give a benefit
• that the treatment is not harmful

You may be persuaded that one can easily be in a position to state with confidence that there is no known better treatment but unless there have been other studies then it might not be possible to claim that the treatment will be beneficial to participants in the trial. At best one may be able to claim that there is reason to believe that some benefit is likely. However if the trial is at an early stage in the research process it may only be possible to say that it is unknown whether there will be a benefit or not and that the purpose of the trial is to see whether there is a benefit. What a clinician says to potential research participants and their parents, if the participant is a child, has to be informative, measured and honest. It is very easy for patients / parents to read too much into a statement from a trusted doctor.

On the issue of potential harm there are similar considerations. If there have been no or few prior studies then the risk profile of a drug or therapy may not be well understood.

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Activity >
Watch and make notes

Watch the film clip below and note down the issues raised by discussants regarding the process of obtaining informed consent.
 

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Discussants identify the challenges of informing children and note the need to have appropriate forms of information that are adequate to the task. It is particularly challenging to inform children about risk in ways that do not frighten them. Several discussants recognise it is possible to help children have an understanding of research by using different forms of information which are accessible to children. Most discussants are of the opinion that it is the parents’ responsibility to make a decision to consent for their child to enter a clinical trial.

It is generally acknowledged that parents need time to:

• reflect on the information they have been given
• have an opportunity to gather their own information and discuss it with others
• have several opportunities to ask questions

In most circumstances it will be a legal requirement to have parental consent to enter a child into a clinical trial. In Europe this is the situation for all children under the age of 16 where it is also regarded as good practice to inform and involve the child participant in the process. In additional to legal consent from the parents, the trial co-ordinators will therefore also seek the child’s assent.

A further issue raised is the challenge of ensuring that parents understand that a clinical trial is not a treatment. This confusion is sometimes called the “therapeutic misconception”. This is the claim that some parents or patients invited to participate in a clinical trial are unable to distinguish between an experimental application of a drug or other intervention and a clinical therapeutic application. One implication is that, if parents have this misunderstanding, then they may not meet the conditions for a valid informed consent. One discussant considers the implications of this and asks whose responsibility it is finally to enter a child into a clinical trial? Clinicians have a professional and ethical responsibility to be satisfied that parents have understood the information about the trial and any associated risks. In extreme circumstances a clinician may have to decide whether it is appropriate to include a child in a clinical trial if the parents hold a mistaken belief about the purposes of the study.

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Activity >
Read & make notes

Read Sammons which summarises some of the current debates on clinical trials with children.

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Ethical issues of clinical trials in children: a European perspective.
H Salmons BMJ 2009 94:474-477

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If you are unable to access the article – move to the next page where the relevant issues are outlined.

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Sammons notes that the EC has produced incentives for clinical research into childhood diseases and the importance of testing medicines specifically for children, on children, is well recognised. It seems the debate has moved from Edwards’ discussion of the justification of the inclusion of children in clinical trials to Sammons’ question as to whether it is unethical to not involve children in clinical trials.

Sammons outlines many of the arguments that this tutorial has covered and introduces some more detail about clinical trials with children. You might have noted:

1. the widespread use of drugs with children which have not been tested on children
2. identification of factors which affect consent, such as financial inducements or clincians’ influence
3. children’s understanding in the assent process

In addition the article discusses trial design and shows some of the ways that it is possible to reduce the invasiveness of trial procedures on children. They make the important point that ‘pain, distress and fear’ should be minimised with children and this is linked to children’s inherent vulnerabilty.

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This tutorial introduced you to the principles of research ethics in general and with specific attention to the ethical challenges of involving children in clinical trials.

Ethics or moral philosophy is concerned with issues of what is right and wrong, good and bad in relation to human action. Ethics is also concerned with the critical evaluation of arguments and judgments about the morality of action.

In the context of research ethics the approaches of moral philosophy are used to analyse the rights and interests of the research subject, the duties and responsibilities of the researcher, as well as the wider public interest in conducting ethical research.

The Declaration of Helsinki, as one of the earliest ethical codes of practice, has had an important influence upon ethical standards in research. Some of the issues raised within Helsinki remain topical and important but the changing field of research requires researchers to reflect on how we justify research ethically.

Research or treatment?

One set of key issues is the identification of the similarities and differences between research and treatment. In particular it is necessary to consider the different standards of justification, including risk and benefit that apply to the two contexts. Treatment aims to provide a direct benefit to the individual patient in circumstances where there is a reasonable degree of certainty that the benefit will apply to the patient and where any risks will be carefully weighed against the benefits. By contrast research can rarely guarantee direct benefit to all research subjects, there will always be disadvantages to participating in research, there may be considerable risks, and there will always be some uncertainty about both risks and benefit.

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The inclusion of children in research also raises particular concerns because of their inherent vulnerability (particularly so for younger children). However recent debates have emphasised that such concerns, although important, must also be balanced against the serious disadvantages of not including children in research.

The paper by Edwards and Macnamee (2005) presents a set of arguments outlining strict limits to the inclusion of children in research. Working through an analysis of their arguments it is possible to see that there are strengths both for and against their position. Although it is possible to support their restrictive approach to including children in research the case becomes weaker in the context of rare childhood disease. The example of Duchenne Muscular Dystrophy (DMD) makes a strong case because this is a disease that only affects children and which affects quality and length of life. To exclude children with DMD from clinical trials seems to condemn them to a progressive and life-limiting disease.

The analysis of the film clips showed an active workshop discussion of the ethical issues of children and research. The discussion identified the following further issues:

• The challenge to clinicians and researchers in ensuring parents/patients understand the difference between research and treatment.
• The challenge of making the necessary justification for including children in a particular research study.
• The complexities of informed consent that allow children to play an informed role according to their age and capacity.
• The particular challenge of informing parents so as to support them in situations when the hope for a cure may distract them from a proper evaluation of the risks and benefits of research.

This tutorial aimed to provide an introduction to the complex issues of research ethics. It aimed to describe ethics as well as engage the student in doing ethics by evaluating real ethical issues in a live ongoing debate. To engage in ethics is to recognise that the task never comes to an end, we must always be prepared to re-evaluate arguments and to see new problems as situations evolve over time.

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Freely available articles

International Ethical Guidelines for Biomedical Research Involving Human Subjects
Council for International Organizations of Medical Sciences (CIOMS) 2002 : pp.63.

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International references on ethics and science
European Commission, 2007
Retrieved 13. August 2007, from http://ec.europa.eu/research/science-society/index.cfm?fuseaction=public.topic&id=362.

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Ethical and legal aspects on clinical trials with children
European Information Network Ethics in Medicine and Biotechnology Eureth.net 2004, Retrieved 08. August 2007, 2007, from http://www.eureth.net/literature/EthicalLegalAspects.pdf.

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CHMP guideline of clinical trials in small populations
European Medicine Agency EMEA, 2006
Retrieved 22 Feb 2010, 2010, from http://www.ema.europa.eu/pdfs/human/ewp/8356105en.pdf.

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Europe’s pediatric rules in force – at last
O’Donnell, P. 2007, Applied Clinical Trials Online

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Rare Diseases as a public health priority
Hagger L; Woods S. Children and research: a risk of double jeopardy? The International Journal of Children’s Rights 2005, 13(1-2), 51-72

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You may have to login or to pay to gain access to the articles below

 

Clinical trials of orphan medicines
B M Buckley, Lancet 2008 371(9629): 2051-2055

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Seen but not heard? Children in clinical trials
E Cave, Medical Lew Review 2010 18:1-27

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Why “Underpowered” Trials are not Necessarily Unethical.
Edwards, S. J. L., R. J. Lilford, et al., Lancet 1997 350: 804-07.

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Children as Guinea Pigs: Historical Perspectives
Lederer, S. 2003, Accountability in Research: Policies & Quality Assurance 10(1): 1.

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Ethical principles and legal requirements for pediatric research in the EU: an analysis of the European normative and legal framework surrounding pediatric clinical trials
Pinxten, W., K. Dierickx, et al. 2009, European Journal of Pediatrics 168(10): 1225-1234.

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The ethics of clinical trials: A child’s view
Rosato, J. 2000, Journal of Law Medicine & Ethics 28(4): 362-378

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Lest we forget… research ethics in children: perhaps onerous, yet absolutely necessary
Brierley J, Larcher V 2010,

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