Marisa Fasanelli,

President of Peter Pan Association (Rome, Italy)

In the past thirty years, paediatric oncology is unquestionably the branch of medicine that has achieved most success in terms of healing, especially in the field of leukaemia. Nevertheless, about 25% of the patients die, 60 to70% of the survivors will have at least one late effect and 30% of these will have more numerous and more serious late effects due to the treatment. Thus there is an urgent need for less harmful radiation and more effective and less toxic new drugs, obtained through clinical studies or clinical trials.

More than 50% of the drugs administered in paediatric oncology are tested only on adults. It is necessary to test new compounds that improve healing rates and decrease the severe long term effects that the treatment can have, by shifting the reasoning from the maximum tolerated dose to the minimum effective dose, to reduce the burden of later consequences and, at the same time, improving the quality of life of the young patients during treatments.

The 2004 European Directive which regulates the testing of new drugs has been developed with the intent to ensure the patients’ safety and rights as well as data integrity. But the legislation is so complicated that in turn it is hampering the process: the costs of trials (administrative costs, insurance and staff) have increased fourfold since 2004. Start-up times for trials are significantly longer (up to 152 days), which in some cases have resulted in the suspension of ongoing studies. The administrative burden, which the legislation places on researchers, led to a 25% overall drop in the number of clinical trials since then.

So the strategic cooperation between researchers and physicians, including parents’ associations and government agencies, ministries and industry is essential to make the process for the acquisition of the new compounds smoother and faster.

The parents, through their European representatives, are joining the chorus of criticism expressed by the academic and industrial world and intend to support their claims to revise the legislation as soon as possible.

Ethical issues of experiments on children give way to heated controversy.  It would be suitable to have a golden rule with precise references and behavioural codes for all occasions. Were it so, we would not be here still discussing it.

Every child is unique

The fact is that every child is unique with his/her own personal and clinical history. So, each time the physician should question him/herself what is in the child’s best interest, to reach a conscious, well thought through and shared decision with the parents, without imposing any further physical or psychological strain on the child.

The number of young patients, as we know, is rather small and since at least 100 patients must be signed on in order for a trial to take place, only high accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately to be generalized to clinical practice. However, there must be a balance between the need for high enrolment in clinical trials and other important factors such as relational factors, psychological factors and ethical issues. Therefore, high recruitment should not be the ultimate goal, but rather “optimal recruitment”. An optimal recruitment takes into account that families have been well informed and are able to make informed decisions whether to enter into a trial or not.

The therapeutic alliance

At the basis of the decision-making process which precedes the signing of the informed consent document, there is the so-called therapeutic alliance, namely the dynamic relationship that begins with the child’s first arrival in the hospital and that is perfected with the development of mutual understanding and sharing of lived experience of the various stages of the treatment process. From this relationship comes the feeling of confidence, entrustment, cooperation, with the common goal of the child’s cure.

The failure of the traditional therapy almost always puts a strain on the relationship between the doctor and the family. When one must make a change of course, it is necessary to redefine the relationship and to ‘get acquainted’ once again.

If the alliance is solid, after a predictable moment of crisis, a new stage of trust will start and proposals for new protocols will be accepted. If the alliance is fragile, it is very likely that there will be a rejection.

The various phases of the trials present different risks and therefore raise different ethical questions. Particular ethical questions arise when (as is increasingly the case in daily practice in phase 3 studies) doctors who recruit young patients are also the same who are directly involved in the patient care. There is a fear that there may be a conflict of interest between the two roles, between the physician and the researcher. It would be more transparent if the two roles were clearly spelled out in the course of the meetings preceding the signing of the consent.

Parents must be fully convinced not only that the doctor will – in any case – give priority to the child’s best interest with respect to the scientific objective he/she  intends to pursue, but also that, if the trial has a significant and emotional toll for the child, the doctor would be ready to withdraw the child.

The doctor, although aware of his/her own experience and competence, should in turn question his/her own motivation, vocation, ideals (too much confidence in the trial may in fact make the doctor less attentive to the reluctance of the parents and the child) and ask the question:
“What does this child mean to me? What do I mean to the child? What are my goals – conscious or subconscious?” In this manner it will be easier to make a decision and accept its consequences in the short, medium and long term.

The logic of individual treatment is therefore a PRIORITY over the scientific imperative of research useful to the community. These two kinds of logic should never be in competition. Both doctors and parents and their child should be convinced of this.

In this triangular relationship, the ability to communicate effectively plays a key role in the informed consent process. Clear and precise communication helps in the decision making process. Informed consent cannot be the result of a single interview, but must be a dynamic, continuous, two-way process, with various phases distributed in intervals, in which there are regular meetings or milestones checking that what has been said, has been fully understood, before progressing to the next stage.

Informed consent – based on the level of information

There is a difference between signing a legal document that does not necessarily presuppose the signatory’s understanding of its content and which is more likely to protect the doctor and the institution that is promoting the research and a valid informed consent, where parents have full awareness of the risks they face.

When parents are faced with a choice, they do not really react to the content of the proposal, but more so to the manner in which it is presented. The main difficulty of communication between people therefore, does not depend on the complexity of the content of the message, but on misunderstandings, prejudice, conflicts and unfavourable emotions. Good communication leads to a willingness and capacity to have good relationships with others. Good comprehensible communication accepts the other person, while a deliberately cryptic communication – often an unconscious expression of defensiveness by the doctor – inevitably raises a wall between people.

The capacity of adapting messages to the needs of the speaker, means being able to grasp feelings, thoughts and emotions – it means being able to adapt to his level of knowledge.

For the more fragile families, we should think of targeted interventions. It is not rare that some parents confuse participation in research with the consent to traditional treatment and that they have somewhat confused ideas about the meaning of randomization or about the various stages of the research.

In many countries parents’ associations are asked to assess the level of understanding of the information given in the documents for informed consent with regards to its form and its substance. They make sure that it is adapted to the age of the patient and can be understood by the families.

It is essential to reduce the number of pages to be read to a maximum of five or six. No one has the perseverance to read and understand a stack of thirty pages of information – especially in a situation of crisis! In the information, the words should be simple, the sentences short, and the grammar elementary. But these conditions are hardly ever met. The authors of the text rarely reach out to the parents and the children. The information about the possibility to participate in randomized trials should be given in good time, so that parents have the opportunity to make an informed decision and take a conscious choice.

There are however emergency situations in which the child’s life is in danger and there is a need to enter a trial immediately, which may be, due to the medical condition of the child, the best possible choice. In these situations, parents are absolutely unable to listen, to understand, to judge; and it would be unethical to “extort” a consensus simply to comply with the rules.  The consent to be given in 24 hours does not express the full awareness of the potential risks of the trial, but is only an expression of trust one has in the doctor.

It is for this reason that it has been proposed to divide the decision making process in two distinct phases: conditional consent and final consent. In the first stage, parents should be given a concise two-page information sheet, with key facts about the trial, in which the benefits and risks related to the side effects of the drugs are explained, the randomization – if applicable -, the protection of sensitive data and, above all, the possibility to withdraw from the trial within 2-4 weeks, along with the option of not signing the consent in the next phase. This document should be signed in the presence of witnesses who would also sign the document.
In the second stage, after two or four weeks, the parents would have at their disposal all the additional information and could sign the final consent in full awareness, providing their consent to the trial, to the transfer of data, to the use of tissues, to their storage according to the needs of the proposed trial.

Phase-I and -II trials are proposed when every other therapeutic attempt has failed: at this point parents are almost always ready to accept anything, even when a few months prior it was unthinkable. They are desperate and are struggling with themselves about whether there is and what is the limit of what can be imposed onto their child.

During the interviews preceding the signing of the informed consent there should be the possibility of negotiating with the doctor about micro decisions on marginal aspects of the therapy. This would give parents the feeling of having some control over certain aspects of their participation in the trial.

Meetings with other parents who are in the same situation should be encouraged, in order to exchange experiences and information with them.

There are countless reasons that lead parents to agree to participate in trials: to cultivate hope, to prolong their child’s life, to have the feeling of having done everything possible to save him/her, to diminish the suffering, and – why not? – there is also the desire to please the doctor!
Enrollment, however, should not be considered an obligation, but an opportunity. It is logical to hope to reap some benefits even though one cannot predict the outcome: it is like buying a lottery ticket.

However, the proposal of a new treatment cannot, be presented as the only possible alternative: “the trial or nothing” or “certain death without the trial and little hope if one participates.” The information given must include the consequences and the risks of the treatment with respect to possible benefits, but also give the option to choose a standard treatment or the possibility of making different life choices, such as not to try new treatments at all.

During the course of the consultation with the physician, every possible hypothesis should be taken into consideration, so that in the future the parent’s minds will not cultivate regrets or the feeling of discriminations. It is important that the decision can be conceived as the result of a collective resolution, in which each person involved takes a part of the responsibility that he or she is capable of taking on. And, this part must be flexible, according to the needs and timing of each person in facing such a serious decision. To facilitate the decision making process it is mandatory to respect the right time of the decision itself: time is a determining factor. It is the time for reflection to evaluate the hardships and risks against the hoped benefits, time to reach mutual understanding and shared decision by all the protagonists of the story.

Patient`s rights

Traditionally parents have always been – for better or for worse – those who have made decisions for their children. Over the past twenty years, this opinion has changed and parents are no longer the highest authority. The Oviedo Convention on Human Rights states that the opinion of the child should be taken into consideration as an increasingly determining factor, taking into account his age and maturity.

The children are therefore bearers of rights and as such have a greater decision-making power for themselves. Even the younger ones should be encouraged to express their feelings and wishes through drawings, play and through any other form of expression. Furthermore it should be noted that, if the child does not agree to participate, his opinion should prevail.

Throughout the illness, but especially in the case in which the illness is terminal, the child develops “antennas”. The child senses the concerns and anxieties of those around him and feels the uneasi-ness of the adults when they speak in his presence and when the child asks certain questions. At some point the child might blame himself or herself for causing it and tries to protect in some way the parents and doctors. We therefore, must remain focused on the child, because the child per-ceives and hears everything: the child is in fact the first person to be concerned.

We need to help parents to have confidence in their child’s abilities, to help them to recognize his/her real needs and residual potentials, to respect his/her limits, to sense his/her wishes, en-couraging and helping him/her to express them, respecting the age and health conditions, his/her need to know or not to know, the right timing, so not to go “beyond” what he/she wants to hear or say.

It also means not to expose the child to unnecessary suffering and to question oneself together with the child about the quality and comfort of his/her life, in order to possibly consider the possi-bility of going back home. For a decision to be ethically founded and acceptable to all, the quality of life of the young patient should be the priority. The child should be allowed to remain “alive” until the end.

For a doctor, the death of a child is always a defeat – something that scares and causes a sense of helplessness. However, if all the options were shared, and every decision was made based on the child’s needs and desires, then it will be easier to accept the loss. Being diligent about making joint decisions will be helpful in dealing with the set-back of losing a child and will allow the physician to preserve his/her self-esteem and to be able to invest in a new case; and will ultimately also help the parents in their time of mourning.

Marisa Fasanelli Baracano – President of Peter Pan Association


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