Final Report Summary - RESPECT (Relating expectations and needs to participation and empowerment of children in clinical trials)
Project context and objectives:
The RESPECT project
The European RESPECT project set out to explore the expectations and needs related to the participation and empowerment of children in clinical trials (CTs). The RESPECT consortium responded to a call from the European Union (EU) Seventh Framework Programme (FP7) for a coordination study concerning Identifying patients' needs in the CTs context (HEALTH-2007-4.1-4). This call requested that three questions be answered:
1. how can patients be better mobilised and empowered?
2. how can patients get the clinical outcomes that really matter to them?
3. how can the patients' needs be integrated into CTs?
The RESPECT project investigated children's participation in CTs. The objective was to determine if there are opportunities to improve recruitment through empowering the children and their parents. The reasons for participation and a model of empowerment were investigated. The reason behind this was the then recent implementation of the European paediatric regulation in 2007.
The paediatric regulation aims to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years; ensuring that medicines for use in children are of high quality, ethically researched and authorised appropriately; and improving the availability of information on the use of medicines for children, without subjecting children to unnecessary trials or delaying the authorisation of medicines for use in adults.
The anticipated benefit has been estimated by the European Academy of Paediatricians to be a social savings of up to EUR 250 million per year through improved healthcare.
The RESPECT consortium aimed to identify:
1. the needs of children and their families as related to CTs of new drugs in Europe
2. methods by which the needs can be translated into empowering and motivating participants in future CTs research.
The aims of the RESPECT project were realised though three objectives, of which the first was to construct a common basis for understanding. The second objective was to collect and analyse various approaches and practices for recruiting patients into CTs in different medical areas and conditions. The third objective was to disseminate these outcomes in order to widen the debate to encourage the adoption of better empowerment and recruitment methodologies for patients in CTs. The RESPECT consortium consisted of experts from the fields of clinical research, patient representation and European paediatric research ethics and regulation. In addition, a wide consultation was conducted by the consortium among other European research projects in this area as well as European academic, industry and regulatory experts. Further consultation and research was also included from the global CTs community.
By drawing together different actors, the project opens the debate on how Europe can improve the participation of children in CTs. Together with the partners in the project, who represent both the research side and the patients' perspective on involvement in paediatric CTs, a stronger, more integrated and more fruitful coordination with different actors can be realised.
Through the dissemination activities of the project, it is intended to contribute to the empowerment of European paediatric patients and their organisations in CTs as well as to assist researchers in defining improved and more appropriate recruitment strategies for paediatric CTs. The project also intends to contribute to the further development of European paediatric research ethics and regulation policy.
The project employed a variety of methodologies for analysing current European patient perspectives on CTs. These methods were chosen and adapted according to the specific groups studied and the needs of the project.
Case study interviews and surveys were employed for child participants and potential participants in CTs, including at times the parents of such children; focus groups were used to evaluate clinical staff views on children in CTs; interviews were employed to understand industry views on children in CTs; group exercises in schools were conducted among children in schools; and surveys were undertaken among members of ethics committees and of patient organisations (POs). The disease areas focused on were epilepsy, growth problems, diabetes, mitochondrial disease, HIV, thalassaemia and cancer. The main emphasis was on obtaining qualitatively rich data that includes the families' own stories of why they agreed to participate and why they continued to participate. All centres were also strongly encouraged to consult with local and national research groups and companies involved in CT research.
The initial project meeting took place in Gothenburg and this was followed by two workshops which took place in Hamburg and focused on developing the methodology for the project and training in case study description as part of work package one (WP1). The of the studies study plans, interview questions, case study manual, questionnaires were developed. Here the survey instruments were discussed and the case studies work-plan finalised. The second workshop was a knowledge base workshop to present the information collected and identify the issues for further consideration in the harmonisation stage. This workshop gave the partners an opportunity to discuss the emerging issues and raise further areas for consideration by the project. As part of this initial stage a literature review was undertaken. The overall project management was provided by the Project Coordinator (PC) and the administrative and financial control resources required to oversee the project as a whole. The PC will responsible for the overall planning and monitoring of the work of the project including tracking the deliverables for the half yearly and final reports. The initial work of the project was to develop a platform for cooperation between the partners. This was achieved through a web-based coordination tool developed (WP2).
The first qualitative data collection was undertaken in WP3 where the objective was to explore the normal procedures for identifying and satisfying patient needs in CTs research. The aim of WP3 was to deepen and extend the knowledge of patient needs, attitudes, expectations, motivations and perceived barriers to participation in CTs. The first source of information was case studies of normal and benchmark best practice in the participating CTs centres. Information was also collected on how families get involved in CTs research and what their 'non-articulated' wishes were for outcomes of the research.
Focus groups with CT staff were arranged with a standard schedule. Following approval by the local ethics committee interviews with families and children currently participating in CTs research was undertaken. The lead partner also undertook to solicit and collate opinions drawn from the internet discussion list and from the web-based questionnaire. Telephone interviews were undertaken with representatives from the pharmaceutical industry and ethics committees.
A web-based survey of POs and groups throughout Europe was undertaken (WP4). In addition a workshop held in Brussels was undertaken in order to identify the concerns and needs of their members and their recommendations as to how empowerment of their members in the CTs landscape could be achieved.
The data and opinions generated from the earlier WPs were then brought together in a harmonisation workshop (WP6). From the integrated sequence of approaches the RESPECT project was able to obtain improved understanding of children and their families' needs concerning CTs. In WP6 the survey findings were categorised and described in order to draw conclusions that can contribute to recommendations for the future development of patient focused CTs research. On the basis of the information gathered it was possible to outline a decision tree for children and their families who are thinking about participation. This aid to decision making outlines the structure for the patient and also for the CTs researcher and was developed into a decision aid tool.
The harmonisation workshop also included a presentation of the education package based on case study data. The objective of the education package was to pilot test a procedure for school education that would describe the needs for CT research and discuss the ethical issues concerning research with children.
The final WP involved dissemination of the RESPECT findings in order to facilitate collaboration and information exchange between different elements of the CTs landscape and to ensure that the results of the project influence the research community and exist in the public domain. Education and outreach formed a major theme of this WP; in addition to a dissemination conference held in Brussels, supporting materials were also developed and distributed. Our public website is one of the main channels for wider public information dissemination and will continue to be maintained in the years that follow the project.
Project results:
The RESPECT project was not designed as a data collection study and as such not all partners were required to interact with patients or gather information directly from individuals. Appropriate ethics review was sought in the cases where data collection was carried out which occurred in mostly in the first period of the project. In the second period the treatment of this data became the main ethical consideration. The RESPECT project exercised its responsibility to ensure that the physical, social and psychological well-being of research participants was not affected by participation in the research. The RESPECT project has sought to protect the rights of those included in the study, taken consideration of their interests, sensitivities and privacy. Our objective has been that the research relationships would be characterised, by trust and integrity. Participation in the research was based on freely given informed consent of those studied. The studies purpose and how the data would be used were explained in appropriate detail and in terms meaningful to children. The participants were made aware of their right to refuse participation whenever and that they did not need to give reasons for refusal. Anonymity and confidentiality were assured and identification of participants was not required and not transmitted between partners.
The main scientific and technological (S&T) results of the RESPECT project
The RESPECT project is not a quantitative study but rather a 'coordinating action' exploring the issues surrounding CTs on children. As part of this process, we conducted about sixty structured interviews and some small-scale surveys of parents and children in hospital outpatient settings in Slovenia, Sweden, Italy and Germany.
Various groups of CT participants were interviewed: diabetes, HIV, epilepsy, mitochondrial disease. The majority of participants who participated in CTs were families who were being treated for their health care needs at the trial site. In the majority of cases, the participant was asked directly by their health care physician. The following case studies were examined:
1. Slovenian parents of children with epilepsy and mitochondrial disease
2. Swedish diabetes vaccine trial, children and parents
3. Italian human immunodeficiency virus (HIV) paediatric patients and their parents
4. Swedish interviews exploring understanding of CTs
5. Child-parent survey (Italian thalassaemia patients)
6. Child-parent survey (Slovenian parents, PHIME study)
7. Child-parent survey (Slovenian parents, HIE study)
8. Healthy adolescent survey (Swedish).
In the RESPECT project, one aspect of the different approaches to understanding participation in CT was a closer investigation into the 'willingness to participate' construct. In a pilot study, questions specifically regarding willingness to participate were extracted from the RESPECT online survey for parents and children in Germany; these were then presented to a convenience sample of medical students, health sciences students and hospital outpatients. In total, 215 questionnaires were returned and psychometric analysis of these responses was carried out to identify the largest explanatory factors for willingness to participate in CTs.
The identified factors were interpreted in terms of factor one (control), factor two (general concerns about participation), factor three (general interest in clinical research) and factor four (personal benefits of participation).
Conclusions
This analysis suggests that the general willingness to participate in clinical research is influenced by the patient's interest and the effort involved to participate. The positive decision to participate in a study depends upon the patient having a basic general knowledge of clinical research and a certain interest in such projects.
The prospect of benefit to others is of great importance but, at the same time, the degree of willingness to participate depends greatly on the extent of personal gain the respondent can derive from participation.
If these respondents were given access to all the information on the use of the data and the results, it would affect their willingness to participate. Apparently, they want to have a say in the study as part of their participation. However, this expectation may reflect the fact that 80% of the respondents were medical or health science students. It would be valuable to follow up this analysis by analysing responses from children and parents.
In planning a CT, the responses indicate that it is important even before the implementation of the study to provide information about possible risks and side effects of the drug to be tested or potential negative consequences from participating in the study. This could be in the form of a brochure or a personal interview.
Trust in doctors: discussion with an expert on the trust concept
During the RESPECT project, doctor-patient trust emerged as an important factor in why people participate or refuse to participate in CTs. Therefore, RESPECT carried out a workshop on trust with an invited expert in this area.
We gathered the comments of families who agreed to participate in CTs and individuals who had never been asked, but it should be noted that we did not get any responses from those who refused when invited to participate or those who withdrew from an ongoing trial. Thus, some of our material sheds light on how people think they would respond to a hypothetical invitation to participate, while those who were in a trial could reflect on why they consented and how they experienced it.
Many of the parents we interviewed saw the trial as a way to get the latest and best medicine for their child (thus misunderstanding the principle of equipoise that is fundamental to CTs). They are disappointed that their child might get the placebo and thus miss out on the latest treatment. A child placed in the control group was seen as a 'guinea pig' in the research, whereas testing the experimental drug was not seen in this light. This indicates that they did not appreciate the importance of randomisation; expecting more personal benefit (which is the normal role of the medical profession). Only the healthy adolescents we surveyed were comfortable with the idea of being a 'guinea pig' for medical research, on the assumption that the risks would be minimised.
Families generally reported that participating in the CT was inconvenient, apart from those who had to come for appointments anyway. Parents said it was worth the time and trouble as long as somebody's child stands to benefit, but we saw repeatedly that the greatest altruism came from those who had not actually been in a trial or whose participation had not been painful or unpleasant. There was clearly a 'tipping point' if this altruism involved subjecting the child to extra pain or distress and the parents in this situation did not always feel that their sacrifices were appreciated sufficiently. They wanted more gratitude and token gestures of appreciation.
When faced with the (real or hypothetical) decision to participate, there was an almost universal desire to get as much information as possible, but those who were in a trial often complained that the information they had received was not easy to understand. Thus, they had to trust the doctors and nurses to guide them in their decision and it was common for parents who had entered their child in a trial to say that they had confidence in the staff and felt that it was a worthwhile study. They were often motivated by a desire to 'pay back' to the medical profession for help already received.
When we surveyed outpatients who had never been in a CT, we found that they were more hesitant at the prospect of participating. They did not feel any obligation to the clinical staff and indicated that there would have to be a positive relationship for them to agree to participate.
Most often, the child does not have much say in the decision and trusts that the parents have understood what the research involves. Thus, trust is a pivotal aspect of consent and it is important that families do not feel that this trust has been broken if the trial was not as they were led to expect. For both the parents and the child, it was not always clear what the trial will involve and it often comes as a surprise that it was time-consuming or painful or that there were side effects. The child is at particular risk of understanding the least while suffering the most distress and some of the older children reflected this when they said they would refuse if asked again.
Parents often saw the trial as an opportunity to get more information on their child's condition. They were eager to see the outcome of the study in total, but were not sure if there was such an opportunity or how they would receive the information. Other parents saw themselves as research partners in making medical progress and wanted to feel that their input was valued. This interest in the research was clearly a motivation for participating in further trials if asked again.
The experience of POs
The RESPECT project conducted an email survey to identify POs' views and perspectives on the level of participation in paediatric CTs and the reasons why children participate in CTs, why they do not participate and what can be done by POs to answer their needs and increase participation in and quality of paediatric CTs. The results showed lack of knowledge of specific figures of paediatric CT per disease.
According to the experience of the POs responding to the survey, participants in CTs are mainly motivated by their direct interest in receiving new treatments. Sometimes the idea of helping other children with similar diseases is also a motivator. In certain cases, they also feel more confident in taking drugs that are being tested than existing drugs that have not been tested on children. The decision made by parents to improve the condition of their child is also one of the reasons that contribute to the participation of children in CTs.
The analysis of the answers provided by POs, sometimes citing direct responses from parents and children involved in CTs, indicate four main types of barriers to participation:
1. emotional barriers
2. ethics and transparency of information
3. practical barriers
4. the relationship with physicians and other entities.
Good practices and what should be done
1. Informing potential participants. The results of the survey highlight a need for a more transparent and structured flow of information by involving in the process physicians, nurses and POs.
2. Strengthening the role of POs. A guiding principle is that patients must be treated as partners in knowledge rather than recipient only of health care treatments, therefore the role of POs needs to be shaped accordingly. POs should be sources of unbiased and reliable information to guarantee transparency in the CT process to parents and children. POs should also be responsible in promoting ethics and principles through formal guidelines at the international level and be in charge of disseminating available information about existing trials, the value of participating in it and sharing information with other POs when the trials are in their same disease area. On the quality of the information disseminated, POs must opt for a 'family-friendly' language and methods. Finally, POs should provide emotional support to parents and practical help. POs should play a role in facilitating logistic problems and reducing obstacles.
3. Responsible role of Institutions. A solid legislation framework is needed. Regulations and legislation will provide a more organised structure to rely on and will allow the development of a family-friendly CT system.
Conclusions
Parent and child friendly CTs are the solution to increase participation and transparency. POs are the key group to produce the change by organising themselves to empower patients involved in CTs and adopt a child-input perspective. For this to happen, better cooperation, education and training need to be further developed at all stakeholder levels. The final expected result will concern the involvement of patients in CTS as partners in knowledge and in the development of true informed consent by families, including by the children themselves where possible.
Physicians and nurses need to develop a family-friendly language and communication strategy, while general practitioners - who already have a trust-based relationship with their patients - are also expected to play a major role by being the first contact among patients and doctors involved in the CT. A solid and reliable legal framework that prescribes international standards and guidelines will provide the political tools for all stakeholders to cooperate better but especially for POs to take the lead in empowering children and motivating them to take part in CTs, by reducing their fears and concerns.
Online survey: POs
This online survey focused more on the way POs operate in the field of paediatric CTs. The results of the survey provide information on three main points: firstly, the type of questions parents of children involved in CT ask to POs, when asked at all; secondly, why patients do and why do not participate in CTs and thirdly, what kind of good practices are already being done and the role of POs at present and for the future.
The questionnaire targeted POs involved in different areas of diseases, among the respondents there were organisations involved in pathologies such as asthma, diabetes, kidney issues, lupus, allergies, thalassaemia, macular degeneration (AMD), haemophilia, cystic fibrosis, Addison, child heart diseases, young rheumatic, Ehlers-Danlos syndrome, epilepsy, mitochondrial disorders, adrenoleukodystrophy, Duchenne muscular dystrophy and some unspecified self-help organisations. The POs that participated in the survey were asked to provide information on their experience of paediatric CTs and specifically to address the issues mentioned above.
The survey aimed to establish what kind of questions parents ask POs to better evaluate what role they (the parents) can play. The results showed that parents do not usually ask questions about CTs directly to POs, but it is more likely that parents tend to enquire with doctors or healthcare professionals involved in the CT. In case of questions asked directly to POs, these helped to understand parents' concerns and limits to participation in CTs.
Several POs received questions about which studies are ongoing in their specific disease area in order to find out whether there are specific treatments being tested for children. This is seen especially with parents of children with severe and usually debilitating diseases or heart disease. In this last case, more information is often requested by parents about cardiac research, in the treatment of pulmonary arterial hypertension, research on anticoagulant medicines or on artificial pacemakers. Some POs registered questions linked with safety and efficacy concerns about the risks involved.
According to the experience of the POs that participated in the survey, parents agree to their child being involved in a CT mainly because they would like immediate benefits from a new treatment, access to new generation of drugs or if they want to ask for an early introduction to these. In some cases parents feel a sense of 'gratitude' for the possibility of accessing new treatments and they are keener in having their child participate.
On the other hand, parents who are not willing to let their children participate in CTs are mainly concerned about risks and side effects. In certain disease areas, parents are more worried for girls because of possible fertility issues in the future. In some cases, logistical problems such as lack of time can be a barrier to participation, especially if the CT requires more visits to hospital to receive the treatments. Parents might be less in favour of invasive CTs but more prone when the trials are part of routine examinations.
These barriers to participation might be the consequence of a general lack of trust in physicians or in the scientific sector. According to one of the respondents, a major role is played by public media, which tend to create a dichotomy between the 'good' (alternative medicines, new-age, free-chemicals) and the 'bad' (conventional medicine, drugs). At the same time, scientific magazines that could provide more scientifically reliable articles are not read and not so accessible to the general public on a wide scale, creating a gap in knowledge.
Good practices
Convincing parents of the usefulness/need of the CT, to better inform them and to increase their interest to cooperate are the objectives of good practices. This can be achieved by educational activities, individually and in groups, such as by organising regular meetings. POs should provide a good level of expertise and structure during these meetings, which can be also organised in order to target children directly. A risk factor in focus groups may be the influence of one parent over the group. Indeed, among the respondents to the survey one PO gave as an example the case in which a parent who was especially negative about a CT could undermine their trust-building programme or, on the other hand when the good approach of one parent can enhance positive emulation.
Role of POs
Participants in the survey were asked to describe what is being done already in their POs and what can be improved. Among the responding POs, some are already quite dynamic in activating mechanisms to increase participation in paediatric CTs. The majority consistently disseminate information through their internal newsletters or magazines to members in letters or articles. The second choice is to liaise with CTs projects, while the third choice is to get involved directly in campaigning and lobbying activities, sometimes at the EU level as well.
Among proposals to improve the role of POs, what emerged is that POs ask for a more active and recognised position as an intermediary in CTs between patients and professionals. POs especially ask to be involved from the beginning in a CT, by helping to recruit participants and presenting them the information as first interlocutor; in this way they can act as a resource both for families and researchers. They further ask to be responsible for developing ethical guidelines and to advocate and campaign for regulations. POs want to play their role of intermediaries among the researchers and patients through platforms that involve all stakeholders in CTs and they want to be the first to disseminate information to other organisations and to patients.
POs are ready to be active players in managing the relationship between paediatric patients and the research sector to improve participation in CTs and to make the experience more empowering for children. To achieve results through good practices, POs ask to be formally recognised as the intermediary among patients and professionals and to act within a common legal framework. They want to be involved all along the process of CTs, starting from recruiting the participant, though information activities and disseminating the results. Reinforcing the role of POs will increase the level of trust towards the research sector. Indeed, both of the surveys conducted by EPF highlighted that parents tend to mistrust based on their lack of - or limited access to - information.
This second survey stressed an additional aspect: the role of the media in creating fallacious perceptions. General media tends to emphasise the importance of natural remedies, creating a negative perception of traditional medicine. This can bias the approach of parents considering involving their children in CTs. At the same time, scientific magazines with more accurate information are not so accessible at the public level. POs can thus be expected to reduce information gaps at the level of parents involved in CTs through education and training, but also at public media level, by pursuing and reinforcing their activities of information dissemination.
The experience of CTs staff
1. Focus group with German clinical research staff: RESPECT conducted a focus group with German researchers and clinicians to explore their concerns about the difficulty of recruiting children to studies that imply some risk for the child.
2. Focus group with Swedish clinical research staff (diabetes): RESPECT ran a focus group with Swedish nurses involved in a diabetes vaccine CT. The discussion material consisted of patient statements drawn from our earlier literature search and case studies indicating why they had participated in a CT, as well as additional statements suggested from the literature review indicating why a patient might refuse to participate.
3. Focus group with Swedish clinical research staff (cystic fibrosis): The clinical staff reported that, because CF is a chronic disorder, they build up a strong relationship with their patients over many years, which makes it easier to encourage them to be in a CT. The team staff reported low dropout rates in their trials, probably because of this strong relationship. They discussed how much harder this would be if they were dealing with, for example, cancer patients who would have recently got a diagnosis and be coming to a clinic where the staff didn't know them. It would be hard to establish trust quickly and their acute condition would make them less willing. Parents would find it tough to make such a decision in this situation.
Interviews and survey with paediatricians
This part of the RESPECT project aimed to explore how paediatricians approach the task of recruiting children and their parents to CTs.
Data collection took place in Nov-Dec 2009. There were four interviews with professors of paediatrics in Sweden, Italy, Germany and the Netherlands. The same questions in the form of a survey were distributed to paediatricians in Slovenia and we received ten responses. These respondents had considerable experience of CTs, recruiting on average 85 participants each (ranging from 10 to 300).
Families' motivations to accept
The expectation of better treatment motivates both the families and the paediatrician. Indeed, the paediatricians commonly reported that they emphasise the extra monitoring and potentially better treatment when encouraging families to participate. As a consequence, a comment was made that some parents may feel that they will not get full and appropriate treatment unless they agree to participate in the CT. The personal relationship with the doctor was considered to have an impact, with the child and the parents wanting to follow the doctor's wishes. In return, the paediatricians were concerned to reduce inconvenience & pain as far as possible and wanted protocols to minimise the number of blood tests the child would undergo.
Explaining CTs
When asked about what families understand about clinical research and whether it is hard to explain about the CT, many of the paediatricians reported that the parents' level of knowledge varies and that children understand even less and can be inattentive. These paediatricians gave vastly different responses when asked how old a child needs to be to give their assent (ranging from 4 to 18 years of age). Particularly problematic are situations where the parent will consent, but the child will not give assent (especially if he or she is rather small); children do not see the necessity for the study.
On the question of explaining risks and benefits, they stressed the importance of being honest, as you would with your own child, with explanations appropriate to the child's age. Listening and responding to the family's questions was considered important. These subtle skills are not available in the ethics committee guidelines.
Payback to participants
More than half of the respondents reported that they give the family information on the results of the study, but in several cases this was only on request. One paediatrician suggested that knowledge is something they could offer when encouraging participation, because the interested parents and children will learn about the research by participating. Interestingly, some of the respondents mentioned that patients would like to see more gratitude from the staff or the sponsor, probably reinforced by token gestures (gifts or treats, such as a meal) for the children.
Recruiting patients: discussion with experienced paediatricians
In January 2010, we held a seminar with the senior paediatricians among the RESPECT project partners, to find out more about their experience in relation to the interview and survey responses we had gathered from other paediatricians.
Barriers to participation
The parents who are most resistant to invitations to enter their child in CTs are the ones for whom the existing treatment is working well and the CT concerns testing different doses or oral versus intravenous administration. They do not want to change anything, so recruitment will be a problem and the CTs will probably have to reduce the sample size required for significance (as they do now for orphan diseases). It may even be necessary to recruit from more countries. Often around half of those asked to participate will refuse. One suggestion was that there should be campaigns (appeals) to the public to raise awareness of CTs and increase the likelihood of participation.
If the parents have no established relationship with the doctor (for example, a mother approached when she has just delivered), only about 20 % will agree to let their child participate. They are usually the more educated mothers who feel research is important and personal benefit to the child is likely. The other 80 % do often come round to the idea later and it is very rare for families to withdraw once they are in a trial. If their child has a chronic disease, they are more likely to participate for altruistic reasons; they feel that they will see reciprocal benefit in the long run.
In the case of chronic diseases, the clinicians already know the patients and may ask them to be in many trials. Indeed, they avoid inviting new patients to participate and wait until they know them better. In any case they would always contact the patient's primary care physician for background information (medical history and also previous compliance to their medical regime). The patient's physician may have little experience of randomised CTs or alternatively have been involved in many trials before. He or she may be asked to join someone else's CT as a satellite trial centre but an alternative is to send the patient(s) to the main trial centre instead. This may be better for the patient in terms of expert monitoring. It means that the patient effectively receives a second opinion on their diagnosis and prognosis, which the primary physician may see as a benefit or (possibly) a threat.
Exclusion
Immigrants tend not to get included in CTs. There is an assumption they will not understand the instructions because of low education, but this may be an assumption by medical staff. We need to be more inclusive and provide cultural mediation, not just translation. There is a European Commission project called European standards on confidentiality and privacy in healthcare among vulnerable patient populations (EuroSOCAP) that is producing guidelines on addressing patients in their strengths instead of focusing on their weaknesses.
In the case of HIV (in which the child contracts their condition from their mother), it has been observed that some mothers refuse to let their child participate because they themselves had a bad experience (such as a rash) with the drug and don't want the child to risk this. Since adherence is important, the clinician will not enter these patients in a CT of a drug they are unlikely to take.
Spontaneous requests
If the patient is on a standard drug and it is not helping, the parents are glad to try something new. In fact, they consistently ask spontaneously to be included in any trials that may be started, especially if their child has a fatal disease. Many parents spontaneously seek information about their child's condition on the internet.
Patients who are more empowered will want to find a CT that suits them. It is possible - at least in United States of America (USA) and Sweden - to respond to an advert in the press or radio recruiting CT participants, but in other countries, these spontaneous applications by patients may not be allowed.
Conclusions from survey and interviews
These responses raise the question of whether the existing good clinical practice guidelines are enough. Just ticking informed consent checklists may not be a guarantee of true informed consent. We cannot be sure whether parents and children have really understood what they are being asked to do or whether they consent instead because they trust the doctor, the nurse or the researcher to do what is in their best interests. This leaves families in a vulnerable position.
There is a risk that some adults (among both clinicians and parents) do not consider the child's opinion to be valid and do not communicate directly with the child. It is important to gain the family's respect and trust by being honest - as one would with one's own child; the clinical staff must give and take feedback before, during and after the trial.
The responses highlight the importance of clinical staff respecting their patients' needs in order to increase willingness and motivation to participate in a CT. It is important to listen to the family's concerns; wherever possible, the clinical staff should strive to reduce distress for the child and keep inconvenience for the family to a minimum.
Physicians are in a unique position to inform trial sponsors about the child's unmet medical needs and to influence which trials are conducted, but it was not clear whether they use this influence; however, they do sometimes emphasise to sponsors that they prefer to avoid too many blood tests on their young patients.
It is important to ensure that families understand the need for research and are respected for their valuable contribution to CTs; randomisation must be clearly explained and the clinical staff must show appreciation, acknowledging that the child is a 'medical hero'.
The experience of CT networks
CT networks: involvement of paediatric patients and their parents
Survey findings
Our consultation shows that only three out of the eight paediatric CT (PCT) networks participating in the survey systematically involve patients and/or POs in their clinical research. Two of these networks are 'disease oriented' and fall in a very specific 'rare diseases' category, while the third (MCRN) is a 'generic' network facilitating the development of medicines that are both safe and effective in the treatment of children.
CVBF-TEDDY highlights the fact that the direct participation of patients in the planning stage of the clinical research depends on the type of study and in particular on the investigated disease: if there is a strong PO (as in the case of thalassaemia and cystic fibrosis), it is more likely that their input is sought from the early stages of the research.
Recruitment is usually carried out within the network's members and/or participating centres; if the number of patients recruited through the network is not sufficient, specialists and/or POs (in the case of rare diseases) are contacted; only occasionally the CT is publicised through advertisements.
Feedback is systematically given only by PENTA, while usually it is encouraged, but not always attainable. The amount of information given to patients depends on the sponsor, but usually data relate only to the general outcome of the trials, while personal information is typically not given.
Examples of best practice are provided by Finpedmed, PENTA and MCRN.
1. Finpedmed developed a national template for providing information on a CT to paediatric patients of all age groups and templates for informed consent in all age groups. They have also developed picture cards to use when providing information on a CT for children.
2. PENTA established youth groups that providing feedback on their HIV infectious status and their medical and social care.
3. MCRN encourages the active involvement of young people and families in the design and delivery of CTs via the MCRN young person's advisory group, or topic specific focus groups.
Conclusions
The European paediatric regulation posed the legal basis for the development of the 'European network of existing national and European networks, investigators and centres with specific expertise in the performance of studies in the paediatric population'. The European Medicines Agency (EMA) was appointed the responsibility to set up such a network and in May 2010, the recognition criteria requirements to become member of the network were agreed on by participants from 38 national research networks and CT centres and the EMA.
CT networks interested in joining the network were invited to complete a self-assessment form (to be updated annually). A total of 33 networks submitted self-assessment forms to the EMA: 18 are now officially members of the European network of paediatric research (Enpr-EMA); one was, at the time of writing, undergoing clarification and 14 do not qualify for membership.
Recognition criteria for self-assessment
The self-assessment form contained the following six criteria that networks should fulfil to be recognised as a member of the Enpr-EMA, namely research experience and ability; network organisation and processes; scientific competencies and capacity to provide expert advice; quality management; training and educational capacity to build competences; and public involvement.
Conclusions
It is sometimes assumed that involving families in making the informed consent material clearer is the closest patients, families and/or POs can get to involvement in the design of CTs, but this report shows that much greater involvement is possible and is already practised by these organisations to some extent.
Public involvement is required by European Authorities.
The inclusion of patients, parents or their organisations in the Networks' activities as one of the qualifying criteria for membership in Enpr-EMA is just one of many examples within the EMA, that includes POs representatives in their various Committees and working groups.
The fact that those networks not qualifying as members of Enpr-EMA are also those that apparently have weaker links with patients is a fact that should not be taken lightly, especially if compared with the very different approach employed by Enpr-EMA member networks that on the other hand more systematically involve patients and their representatives. Making patients able to have a direct input in the design and execution of the trial, as well as in the prioritisation of needs, will motivate their participation. In addition, a closer cooperation between researchers and children and/or their representatives as active research partners enriches the understanding of the medical condition and the outcomes.
There are many initiatives aimed at promoting and encouraging patient and public involvement in clinical research and many examples on how to make these initiatives successful: PENTA, MCRN UK, ECFS-CTN. These networks prove that the involvement of the public does work.
The experience of ethics committees
Survey on the involvement of European ethics committees in paediatric research
The CT-Directive introduced a number of measures to harmonise the ethical review of CTs and facilitate clinical research. It required member states (MS) to legally establish ethics committees, including obligations and specifications, formal procedures and timelines, composition and competencies. Specific provisions were also adopted for reviewing CT protocols including children. However, due to the nature and legal force of a Directive, MS had some flexibility in implementing its provisions in their national legislation. Thus, ethical review procedures and the amount and quality of publicly available information vary significantly among European countries.
To evaluate the impact of the new European paediatric regulatory framework on the activities of ethics committees charged with reviewing paediatric research protocols, the TEDDY network of excellence and RESPECT set up an inventory of ethics committees existing in Europe and conducted a survey among them on their approach to paediatric trials.
Impact of the European paediatric regulation and European ethical recommendations
Overall, ethical committees (ECs) recognised, as possible effects of the new European paediatric regulatory framework, the increased involvement of children in clinical research and, thus, an increase in the number of medicines tailored for children, as well as better-designed paediatric trials and more multicentre paediatric clinical studies.
When asked about the influences of the new regulatory framework on their work, around two-thirds of the 73 responding ECs reported no impact or low impact from the paediatric regulation or the European ethical recommendations and under 10 % acknowledged a high impact.
This low impact was particularly true of ECs operating in EU-15 MS (Belgium, France, Germany, Ireland, Italy, Luxembourg, Portugal, Spain, Sweden and the Netherlands). In contrast, one-third of ECs in new EU MS (Cyprus, Czech Republic, Estonia, Latvia, Malta, Poland) declared a high impact of the paediatric regulation and most acknowledged either high or sufficient impact of the European ethical recommendations. These data suggest that ECs in the new EU MS are more actively involved in efforts for integration and harmonisation towards EU research and health norms and systems than EU-15 ethics committees.
The major influences recognised by ECs were: the creation of new rules for reviewing paediatric protocols and sometimes changes in the EC organisation; increased quality and number of paediatric protocols and especially the increased time needed to review these protocols. Lesser effects included increased attention to paediatric protocols; increased facility to carry out paediatric trials; and the necessity to specify ethical requirements. It was also underlined that it is difficult to adapt information to parents and children in accordance with the new requirements.
Main issues to be dealt with by ECs
Looking at the opinions of ECs on the major issues to be dealt with under the regulatory framework, about half of our sample identified the increased need for additional expertise to evaluate paediatric protocols and for measures to minimize pain, distress and fear of children. It was stressed that there is still a lack of knowledge regarding the risks and burdens that are acceptable for children in different age groups. Complexity in evaluating inclusion/exclusion criteria, risk/benefit balance and consent/assent procedures were also highlighted as main concerns.
Training and networking for ECs
Only 30 % percent of the 73 respondents indicated that they had participated in initiatives in the field of paediatric research and those who did mainly took part in conferences and, to a lesser extent, training activities. Moreover, a significant number of ethics committees operating in Europe showed interest in initiatives related to paediatric research, preferring means such as training at national and local level and networking among ECs. Debates and conferences (at the national level) and educational initiatives supported by European institutions were also of interest. Three-quarters of those ethics committees interested in networking belong to the EU-15, while the remainder are established in new MS (Cyprus, Czech Republic, Estonia, Latvia, Malta, Poland).
Conclusions
This survey demonstrated that there is a lack of knowledge of the European paediatric regulatory framework among ethics committees and that their awareness of ethical issues related to paediatric research is limited, reflecting their low level of involvement in paediatric research, especially in terms of training, education and other similar activities.
Given that ECs are one of the most important actors in guaranteeing the safety, rights and well-being of children involved in clinical research, it is of primary importance to increase their competence and their involvement in paediatric research and to promote the implementation of the European ethical recommendations at the local level. In this context, training and education in the field of ethics of paediatric clinical research should be an important objective.
Networking may be a fundamental tool to enhance collaboration and experiences and information exchange. It should be particularly important to promote these initiatives in the new MS, where the number of CTs is increasing.
One possible relevant result of networking could be the development of a comprehensive guide practically addressing paediatric ethical issues in accordance with all the relevant international and European ethical and legal sources. This guide, chaired at the EMA level, should address all those specific ethical issues related to paediatrics: information/authorisation-assent process, paediatric expertise of ethics committees in charge of reviewing paediatric protocols (including training and education of the members of the ECs), use of placebo, compensation for damage, as well as other specific aspects to be considered in reviewing paediatric protocols.
Swedish central ethical review board interview
Background: the structure of Swedish ethics committees
In Sweden there is one central ethical review board, which was founded in 2004 and six regional boards, which are situated at the Universities of Gothenburg, Linköping, Lund, Umeå and Uppsala and at the Karolinska Institute in Stockholm.
These are independent authorities, divided into two or more sections that make decisions on behalf of the regional board. Each section is headed by a chairperson who is a judge or has been one. The sections have ten members with scientific qualifications and five members representing the general public. It is important that every application should be processed by members who have sufficient expert knowledge. The scientific members are therefore highly qualified. All members and their substitutes are appointed by the government. Each of the sections is expected to have 10 to 12 meetings annually.
Within each section, a scientific secretary is appointed from among the scientific members. Together with the chairperson of the sections, the scientific secretaries are responsible for processing cases and dealing with them.
Conclusions
This interview confirmed the picture of a lack of knowledge among ethics committees of the European paediatric regulatory framework. It also reflects the closed structure of ethics committees and their reluctance to include parties who could contribute to their work.
The experience of the pharmaceutical industry
RESPECT conducted four phone interviews with senior managers in the area of protocol feasibility and patient enrolment within both small and large multinational pharmaceutical companies.
It should be pointed out that pharma companies lacking a strong patient focus were less likely to agree to be interviewed and it was generally difficult to make contact even with companies who appeared to have admirable practices, judging from the materials they made available in the public domain, because of standard corporate policies about protecting company-confidential information.
Our interviews gave a snapshot of pharma companies with a commitment to facilitating patients' participation in paediatric CTs. They are aware of the importance of keeping families informed and reducing the burden for the child, but they still have to improve their contacts with POs, for example in allowing them to contribute by reviewing the CT protocols.
Main conclusions from the RESPECT findings
Many of the parents we interviewed saw the trial as a way to get the latest and best medicine for their child (thus misunderstanding the principle of equipoise that is fundamental to CTs). Both children and parents were surprised to find that some of the procedures were painful.
Paediatricians reported that parents did not always understand the difference between CTs and regular treatment. They felt that many parents did not see the importance of medical research and did not always have an altruistic attitude. Longer-term participants are no longer able to identify differences between their normal treatment and the CT.
When faced with the decision to participate, families identified a need to trust the doctors and nurses as a motivation for participation. However, other parents saw themselves as research partners in the trial and wanted to feel that their input was valued, although they did not always feel that their contribution was appreciated sufficiently. They wanted to receive the study results but several paediatricians confirmed that they do not inform parents about the results unless specifically asked.
Several POs reported that they were ill equipped to give input on which trials and which outcomes have the highest priority for their members. This is something that could be improved through surveys of their members as a basis for contact with pharma companies.
We found good examples of trials where patients felt empowered to make valuable contributions. We also found POs giving input into trial design and protocols, helping to define outcome measures and to recruit trial participants, as well as pharma companies making their trial results accessible to all via their website. It is important to ensure that families understand the need for research and are respected for their valuable contribution to the improved safety of medicines for children.
Potential impact:
The project has contributed towards the impacts listed in the original work programme. The major impact of this project has been on the promotion of CTs for the development of innovative medicines to improve child health and treat paediatric diseases. We have identified areas of cooperation between different partners in the CTs landscape which will help to make CTs more effective and thus encourage greater innovation and industry development.
This project has created the possibility of cooperation wherein greater participation in CTs will be achieved through identifying the RESPECT tools and mechanisms required to empower patients and promote a debate on the benefits of biotechnology. The project has advanced our understanding of how to more efficiently promote good clinical practice in CTs research through various debates between different actors within this field.
The lack of participants in CTs research, especially children, has been a major bottleneck to the development of new medicines. Improved competitiveness of the European-based pharmaceutical industry through releasing this bottleneck has been addressed at various meetings.
The project has lead to the development of a set of norms and standards for CTs, which in its turn will lead to the accelerated development of new or improved medicines for child diseases. Moreover, the project has had an impact on improving links between research organisations, patient representatives and industry.
Account has been taken of other national or international research activities in this field through the broad networking with the partners. The RESPECT partnership has been able to take advantage of the close link to other networks within the European framework and this has ensured that all our discussions have been included in the debate on needs of the paediatric CTs participants. Working closely with other network projects and with our approach to a broad membership of the dissemination workshop in Brussels which was held at the end of the project has ensured the high impact of the project.
Through close contacts with POs and through the projects web page the project has encouraged an informed societal debate on the benefits and risk of participation and the eventual benefits of an improved biotechnology industry.
The educational packages and decision aid which have been developed are made available through our dissemination activities and through the web site. These will encourage further research and development in this area and ultimately greater participation of people in CTs research. The project has taken a European (rather than a national or local) approach which has made it possible for the project to address the concerns of patient needs in a research are that is increasingly European. It is only at the European level that legislation can be effective in changing the way that CTs will be carried out. It is only at the European level that requirements can be set for industry and we can develop a broad based strong CTs landscape which will promote innovative medicine development in Europe. This will form the basis upon which the industry will grow. This is particularly true for the small to medium sized businesses who will, due to the need to minimise risk capital, want to stay within the European framework.
The positive impact of information sharing
According to the recent Eurobarometer survey in 2006, one in two Europeans believe that biotechnology will improve their quality of life. The survey showed widespread support for medical and industrial applications of biotechnology therefore the situation has been ripe for the promotion of increased participation in CTs. The positive impact of the RESPECT project will be seen as the debate on the benefits and risks of participation between different stakeholders will identify the benefits and risk of CTs participation.
All centres have been strongly encouraged to work in partnership with local and national research groups and companies involved in CT research. This liaison has enhanced an important consultative role for several partners.
The methodology and requirements for generating empowerment have been identified and the RESPECT project has developed professional materials such as a book, decision aid and training packages that will ensure that individuals and those professionals who work with CTs have the opportunity to utilise the projects findings. A European dissemination conference was hosted by the project to ensure dissemination to policy makers, service providers and service users. In addition, the production of training packages, together with the RESPECT website has provided a wider dissemination of the issues.
The results of the RESPECT project have been published in the literature and will continue to be the basis of further publications. RESPECT will maintain a website after the project has ended so that it acts as a reference database for others working in the same field. Maximum use has been made of Community/International Clinical Congresses to discuss the outcomes of the study and to disseminate the results as widely as possible to all within the European CTs landscape. All partners have contributed throughout Europe to the dissemination information about the project and its results at conferences and seminars.
Contribution to standards
The aim of the project has been that the results will contribute to international standards of good clinical practice in CTs with children. This will be further encouraged through our publications.
Contributions to policy development
The project results have, via the dissemination activities, fed into the development of policy in this area. As the impact of the new regulations of the testing of medicines for children takes effect policy will also need to be developed. The project has been timely in that the results are able to inform and influence the development of those policies throughout Europe. Comments were sent to the rapporteur at the EC concerning the concept paper for public consultation on the revision of the CTs directive 2001/20/EC.
This project has contributed to the coordination of high quality research by going beyond the current state of knowledge and identifying the needs and motivations of children and their families when participating in CTs. The project has drawn together different actors in an open debate on the how Europe can be more encouraging to the participation of children in CTs. The project workshops have been open to everyone in the field and this has meant that greater networking could be possible. Together with the partners in the project who represent both the research side and the patients side of the debate a stronger and more fruitful coordination with different actors having an equal role has been realised. We believe that the project will continue to benefit the work programme by being able to support the health theme across a number of areas. The results will be directly implemented by the clinical partners. This will have a snowball effect as the benefits of the approach become evident. The results will be applicable to all medications and all medical conditions. The results will also be transferable to adult CTs as the relevance of the needs approach and empowerment of the patient will be applicable to the adult patient groups.
Project website: http://www.patientneeds.eu
The RESPECT project
The European RESPECT project set out to explore the expectations and needs related to the participation and empowerment of children in clinical trials (CTs). The RESPECT consortium responded to a call from the European Union (EU) Seventh Framework Programme (FP7) for a coordination study concerning Identifying patients' needs in the CTs context (HEALTH-2007-4.1-4). This call requested that three questions be answered:
1. how can patients be better mobilised and empowered?
2. how can patients get the clinical outcomes that really matter to them?
3. how can the patients' needs be integrated into CTs?
The RESPECT project investigated children's participation in CTs. The objective was to determine if there are opportunities to improve recruitment through empowering the children and their parents. The reasons for participation and a model of empowerment were investigated. The reason behind this was the then recent implementation of the European paediatric regulation in 2007.
The paediatric regulation aims to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years; ensuring that medicines for use in children are of high quality, ethically researched and authorised appropriately; and improving the availability of information on the use of medicines for children, without subjecting children to unnecessary trials or delaying the authorisation of medicines for use in adults.
The anticipated benefit has been estimated by the European Academy of Paediatricians to be a social savings of up to EUR 250 million per year through improved healthcare.
The RESPECT consortium aimed to identify:
1. the needs of children and their families as related to CTs of new drugs in Europe
2. methods by which the needs can be translated into empowering and motivating participants in future CTs research.
The aims of the RESPECT project were realised though three objectives, of which the first was to construct a common basis for understanding. The second objective was to collect and analyse various approaches and practices for recruiting patients into CTs in different medical areas and conditions. The third objective was to disseminate these outcomes in order to widen the debate to encourage the adoption of better empowerment and recruitment methodologies for patients in CTs. The RESPECT consortium consisted of experts from the fields of clinical research, patient representation and European paediatric research ethics and regulation. In addition, a wide consultation was conducted by the consortium among other European research projects in this area as well as European academic, industry and regulatory experts. Further consultation and research was also included from the global CTs community.
By drawing together different actors, the project opens the debate on how Europe can improve the participation of children in CTs. Together with the partners in the project, who represent both the research side and the patients' perspective on involvement in paediatric CTs, a stronger, more integrated and more fruitful coordination with different actors can be realised.
Through the dissemination activities of the project, it is intended to contribute to the empowerment of European paediatric patients and their organisations in CTs as well as to assist researchers in defining improved and more appropriate recruitment strategies for paediatric CTs. The project also intends to contribute to the further development of European paediatric research ethics and regulation policy.
The project employed a variety of methodologies for analysing current European patient perspectives on CTs. These methods were chosen and adapted according to the specific groups studied and the needs of the project.
Case study interviews and surveys were employed for child participants and potential participants in CTs, including at times the parents of such children; focus groups were used to evaluate clinical staff views on children in CTs; interviews were employed to understand industry views on children in CTs; group exercises in schools were conducted among children in schools; and surveys were undertaken among members of ethics committees and of patient organisations (POs). The disease areas focused on were epilepsy, growth problems, diabetes, mitochondrial disease, HIV, thalassaemia and cancer. The main emphasis was on obtaining qualitatively rich data that includes the families' own stories of why they agreed to participate and why they continued to participate. All centres were also strongly encouraged to consult with local and national research groups and companies involved in CT research.
The initial project meeting took place in Gothenburg and this was followed by two workshops which took place in Hamburg and focused on developing the methodology for the project and training in case study description as part of work package one (WP1). The of the studies study plans, interview questions, case study manual, questionnaires were developed. Here the survey instruments were discussed and the case studies work-plan finalised. The second workshop was a knowledge base workshop to present the information collected and identify the issues for further consideration in the harmonisation stage. This workshop gave the partners an opportunity to discuss the emerging issues and raise further areas for consideration by the project. As part of this initial stage a literature review was undertaken. The overall project management was provided by the Project Coordinator (PC) and the administrative and financial control resources required to oversee the project as a whole. The PC will responsible for the overall planning and monitoring of the work of the project including tracking the deliverables for the half yearly and final reports. The initial work of the project was to develop a platform for cooperation between the partners. This was achieved through a web-based coordination tool developed (WP2).
The first qualitative data collection was undertaken in WP3 where the objective was to explore the normal procedures for identifying and satisfying patient needs in CTs research. The aim of WP3 was to deepen and extend the knowledge of patient needs, attitudes, expectations, motivations and perceived barriers to participation in CTs. The first source of information was case studies of normal and benchmark best practice in the participating CTs centres. Information was also collected on how families get involved in CTs research and what their 'non-articulated' wishes were for outcomes of the research.
Focus groups with CT staff were arranged with a standard schedule. Following approval by the local ethics committee interviews with families and children currently participating in CTs research was undertaken. The lead partner also undertook to solicit and collate opinions drawn from the internet discussion list and from the web-based questionnaire. Telephone interviews were undertaken with representatives from the pharmaceutical industry and ethics committees.
A web-based survey of POs and groups throughout Europe was undertaken (WP4). In addition a workshop held in Brussels was undertaken in order to identify the concerns and needs of their members and their recommendations as to how empowerment of their members in the CTs landscape could be achieved.
The data and opinions generated from the earlier WPs were then brought together in a harmonisation workshop (WP6). From the integrated sequence of approaches the RESPECT project was able to obtain improved understanding of children and their families' needs concerning CTs. In WP6 the survey findings were categorised and described in order to draw conclusions that can contribute to recommendations for the future development of patient focused CTs research. On the basis of the information gathered it was possible to outline a decision tree for children and their families who are thinking about participation. This aid to decision making outlines the structure for the patient and also for the CTs researcher and was developed into a decision aid tool.
The harmonisation workshop also included a presentation of the education package based on case study data. The objective of the education package was to pilot test a procedure for school education that would describe the needs for CT research and discuss the ethical issues concerning research with children.
The final WP involved dissemination of the RESPECT findings in order to facilitate collaboration and information exchange between different elements of the CTs landscape and to ensure that the results of the project influence the research community and exist in the public domain. Education and outreach formed a major theme of this WP; in addition to a dissemination conference held in Brussels, supporting materials were also developed and distributed. Our public website is one of the main channels for wider public information dissemination and will continue to be maintained in the years that follow the project.
Project results:
The RESPECT project was not designed as a data collection study and as such not all partners were required to interact with patients or gather information directly from individuals. Appropriate ethics review was sought in the cases where data collection was carried out which occurred in mostly in the first period of the project. In the second period the treatment of this data became the main ethical consideration. The RESPECT project exercised its responsibility to ensure that the physical, social and psychological well-being of research participants was not affected by participation in the research. The RESPECT project has sought to protect the rights of those included in the study, taken consideration of their interests, sensitivities and privacy. Our objective has been that the research relationships would be characterised, by trust and integrity. Participation in the research was based on freely given informed consent of those studied. The studies purpose and how the data would be used were explained in appropriate detail and in terms meaningful to children. The participants were made aware of their right to refuse participation whenever and that they did not need to give reasons for refusal. Anonymity and confidentiality were assured and identification of participants was not required and not transmitted between partners.
The main scientific and technological (S&T) results of the RESPECT project
The RESPECT project is not a quantitative study but rather a 'coordinating action' exploring the issues surrounding CTs on children. As part of this process, we conducted about sixty structured interviews and some small-scale surveys of parents and children in hospital outpatient settings in Slovenia, Sweden, Italy and Germany.
Various groups of CT participants were interviewed: diabetes, HIV, epilepsy, mitochondrial disease. The majority of participants who participated in CTs were families who were being treated for their health care needs at the trial site. In the majority of cases, the participant was asked directly by their health care physician. The following case studies were examined:
1. Slovenian parents of children with epilepsy and mitochondrial disease
2. Swedish diabetes vaccine trial, children and parents
3. Italian human immunodeficiency virus (HIV) paediatric patients and their parents
4. Swedish interviews exploring understanding of CTs
5. Child-parent survey (Italian thalassaemia patients)
6. Child-parent survey (Slovenian parents, PHIME study)
7. Child-parent survey (Slovenian parents, HIE study)
8. Healthy adolescent survey (Swedish).
In the RESPECT project, one aspect of the different approaches to understanding participation in CT was a closer investigation into the 'willingness to participate' construct. In a pilot study, questions specifically regarding willingness to participate were extracted from the RESPECT online survey for parents and children in Germany; these were then presented to a convenience sample of medical students, health sciences students and hospital outpatients. In total, 215 questionnaires were returned and psychometric analysis of these responses was carried out to identify the largest explanatory factors for willingness to participate in CTs.
The identified factors were interpreted in terms of factor one (control), factor two (general concerns about participation), factor three (general interest in clinical research) and factor four (personal benefits of participation).
Conclusions
This analysis suggests that the general willingness to participate in clinical research is influenced by the patient's interest and the effort involved to participate. The positive decision to participate in a study depends upon the patient having a basic general knowledge of clinical research and a certain interest in such projects.
The prospect of benefit to others is of great importance but, at the same time, the degree of willingness to participate depends greatly on the extent of personal gain the respondent can derive from participation.
If these respondents were given access to all the information on the use of the data and the results, it would affect their willingness to participate. Apparently, they want to have a say in the study as part of their participation. However, this expectation may reflect the fact that 80% of the respondents were medical or health science students. It would be valuable to follow up this analysis by analysing responses from children and parents.
In planning a CT, the responses indicate that it is important even before the implementation of the study to provide information about possible risks and side effects of the drug to be tested or potential negative consequences from participating in the study. This could be in the form of a brochure or a personal interview.
Trust in doctors: discussion with an expert on the trust concept
During the RESPECT project, doctor-patient trust emerged as an important factor in why people participate or refuse to participate in CTs. Therefore, RESPECT carried out a workshop on trust with an invited expert in this area.
We gathered the comments of families who agreed to participate in CTs and individuals who had never been asked, but it should be noted that we did not get any responses from those who refused when invited to participate or those who withdrew from an ongoing trial. Thus, some of our material sheds light on how people think they would respond to a hypothetical invitation to participate, while those who were in a trial could reflect on why they consented and how they experienced it.
Many of the parents we interviewed saw the trial as a way to get the latest and best medicine for their child (thus misunderstanding the principle of equipoise that is fundamental to CTs). They are disappointed that their child might get the placebo and thus miss out on the latest treatment. A child placed in the control group was seen as a 'guinea pig' in the research, whereas testing the experimental drug was not seen in this light. This indicates that they did not appreciate the importance of randomisation; expecting more personal benefit (which is the normal role of the medical profession). Only the healthy adolescents we surveyed were comfortable with the idea of being a 'guinea pig' for medical research, on the assumption that the risks would be minimised.
Families generally reported that participating in the CT was inconvenient, apart from those who had to come for appointments anyway. Parents said it was worth the time and trouble as long as somebody's child stands to benefit, but we saw repeatedly that the greatest altruism came from those who had not actually been in a trial or whose participation had not been painful or unpleasant. There was clearly a 'tipping point' if this altruism involved subjecting the child to extra pain or distress and the parents in this situation did not always feel that their sacrifices were appreciated sufficiently. They wanted more gratitude and token gestures of appreciation.
When faced with the (real or hypothetical) decision to participate, there was an almost universal desire to get as much information as possible, but those who were in a trial often complained that the information they had received was not easy to understand. Thus, they had to trust the doctors and nurses to guide them in their decision and it was common for parents who had entered their child in a trial to say that they had confidence in the staff and felt that it was a worthwhile study. They were often motivated by a desire to 'pay back' to the medical profession for help already received.
When we surveyed outpatients who had never been in a CT, we found that they were more hesitant at the prospect of participating. They did not feel any obligation to the clinical staff and indicated that there would have to be a positive relationship for them to agree to participate.
Most often, the child does not have much say in the decision and trusts that the parents have understood what the research involves. Thus, trust is a pivotal aspect of consent and it is important that families do not feel that this trust has been broken if the trial was not as they were led to expect. For both the parents and the child, it was not always clear what the trial will involve and it often comes as a surprise that it was time-consuming or painful or that there were side effects. The child is at particular risk of understanding the least while suffering the most distress and some of the older children reflected this when they said they would refuse if asked again.
Parents often saw the trial as an opportunity to get more information on their child's condition. They were eager to see the outcome of the study in total, but were not sure if there was such an opportunity or how they would receive the information. Other parents saw themselves as research partners in making medical progress and wanted to feel that their input was valued. This interest in the research was clearly a motivation for participating in further trials if asked again.
The experience of POs
The RESPECT project conducted an email survey to identify POs' views and perspectives on the level of participation in paediatric CTs and the reasons why children participate in CTs, why they do not participate and what can be done by POs to answer their needs and increase participation in and quality of paediatric CTs. The results showed lack of knowledge of specific figures of paediatric CT per disease.
According to the experience of the POs responding to the survey, participants in CTs are mainly motivated by their direct interest in receiving new treatments. Sometimes the idea of helping other children with similar diseases is also a motivator. In certain cases, they also feel more confident in taking drugs that are being tested than existing drugs that have not been tested on children. The decision made by parents to improve the condition of their child is also one of the reasons that contribute to the participation of children in CTs.
The analysis of the answers provided by POs, sometimes citing direct responses from parents and children involved in CTs, indicate four main types of barriers to participation:
1. emotional barriers
2. ethics and transparency of information
3. practical barriers
4. the relationship with physicians and other entities.
Good practices and what should be done
1. Informing potential participants. The results of the survey highlight a need for a more transparent and structured flow of information by involving in the process physicians, nurses and POs.
2. Strengthening the role of POs. A guiding principle is that patients must be treated as partners in knowledge rather than recipient only of health care treatments, therefore the role of POs needs to be shaped accordingly. POs should be sources of unbiased and reliable information to guarantee transparency in the CT process to parents and children. POs should also be responsible in promoting ethics and principles through formal guidelines at the international level and be in charge of disseminating available information about existing trials, the value of participating in it and sharing information with other POs when the trials are in their same disease area. On the quality of the information disseminated, POs must opt for a 'family-friendly' language and methods. Finally, POs should provide emotional support to parents and practical help. POs should play a role in facilitating logistic problems and reducing obstacles.
3. Responsible role of Institutions. A solid legislation framework is needed. Regulations and legislation will provide a more organised structure to rely on and will allow the development of a family-friendly CT system.
Conclusions
Parent and child friendly CTs are the solution to increase participation and transparency. POs are the key group to produce the change by organising themselves to empower patients involved in CTs and adopt a child-input perspective. For this to happen, better cooperation, education and training need to be further developed at all stakeholder levels. The final expected result will concern the involvement of patients in CTS as partners in knowledge and in the development of true informed consent by families, including by the children themselves where possible.
Physicians and nurses need to develop a family-friendly language and communication strategy, while general practitioners - who already have a trust-based relationship with their patients - are also expected to play a major role by being the first contact among patients and doctors involved in the CT. A solid and reliable legal framework that prescribes international standards and guidelines will provide the political tools for all stakeholders to cooperate better but especially for POs to take the lead in empowering children and motivating them to take part in CTs, by reducing their fears and concerns.
Online survey: POs
This online survey focused more on the way POs operate in the field of paediatric CTs. The results of the survey provide information on three main points: firstly, the type of questions parents of children involved in CT ask to POs, when asked at all; secondly, why patients do and why do not participate in CTs and thirdly, what kind of good practices are already being done and the role of POs at present and for the future.
The questionnaire targeted POs involved in different areas of diseases, among the respondents there were organisations involved in pathologies such as asthma, diabetes, kidney issues, lupus, allergies, thalassaemia, macular degeneration (AMD), haemophilia, cystic fibrosis, Addison, child heart diseases, young rheumatic, Ehlers-Danlos syndrome, epilepsy, mitochondrial disorders, adrenoleukodystrophy, Duchenne muscular dystrophy and some unspecified self-help organisations. The POs that participated in the survey were asked to provide information on their experience of paediatric CTs and specifically to address the issues mentioned above.
The survey aimed to establish what kind of questions parents ask POs to better evaluate what role they (the parents) can play. The results showed that parents do not usually ask questions about CTs directly to POs, but it is more likely that parents tend to enquire with doctors or healthcare professionals involved in the CT. In case of questions asked directly to POs, these helped to understand parents' concerns and limits to participation in CTs.
Several POs received questions about which studies are ongoing in their specific disease area in order to find out whether there are specific treatments being tested for children. This is seen especially with parents of children with severe and usually debilitating diseases or heart disease. In this last case, more information is often requested by parents about cardiac research, in the treatment of pulmonary arterial hypertension, research on anticoagulant medicines or on artificial pacemakers. Some POs registered questions linked with safety and efficacy concerns about the risks involved.
According to the experience of the POs that participated in the survey, parents agree to their child being involved in a CT mainly because they would like immediate benefits from a new treatment, access to new generation of drugs or if they want to ask for an early introduction to these. In some cases parents feel a sense of 'gratitude' for the possibility of accessing new treatments and they are keener in having their child participate.
On the other hand, parents who are not willing to let their children participate in CTs are mainly concerned about risks and side effects. In certain disease areas, parents are more worried for girls because of possible fertility issues in the future. In some cases, logistical problems such as lack of time can be a barrier to participation, especially if the CT requires more visits to hospital to receive the treatments. Parents might be less in favour of invasive CTs but more prone when the trials are part of routine examinations.
These barriers to participation might be the consequence of a general lack of trust in physicians or in the scientific sector. According to one of the respondents, a major role is played by public media, which tend to create a dichotomy between the 'good' (alternative medicines, new-age, free-chemicals) and the 'bad' (conventional medicine, drugs). At the same time, scientific magazines that could provide more scientifically reliable articles are not read and not so accessible to the general public on a wide scale, creating a gap in knowledge.
Good practices
Convincing parents of the usefulness/need of the CT, to better inform them and to increase their interest to cooperate are the objectives of good practices. This can be achieved by educational activities, individually and in groups, such as by organising regular meetings. POs should provide a good level of expertise and structure during these meetings, which can be also organised in order to target children directly. A risk factor in focus groups may be the influence of one parent over the group. Indeed, among the respondents to the survey one PO gave as an example the case in which a parent who was especially negative about a CT could undermine their trust-building programme or, on the other hand when the good approach of one parent can enhance positive emulation.
Role of POs
Participants in the survey were asked to describe what is being done already in their POs and what can be improved. Among the responding POs, some are already quite dynamic in activating mechanisms to increase participation in paediatric CTs. The majority consistently disseminate information through their internal newsletters or magazines to members in letters or articles. The second choice is to liaise with CTs projects, while the third choice is to get involved directly in campaigning and lobbying activities, sometimes at the EU level as well.
Among proposals to improve the role of POs, what emerged is that POs ask for a more active and recognised position as an intermediary in CTs between patients and professionals. POs especially ask to be involved from the beginning in a CT, by helping to recruit participants and presenting them the information as first interlocutor; in this way they can act as a resource both for families and researchers. They further ask to be responsible for developing ethical guidelines and to advocate and campaign for regulations. POs want to play their role of intermediaries among the researchers and patients through platforms that involve all stakeholders in CTs and they want to be the first to disseminate information to other organisations and to patients.
POs are ready to be active players in managing the relationship between paediatric patients and the research sector to improve participation in CTs and to make the experience more empowering for children. To achieve results through good practices, POs ask to be formally recognised as the intermediary among patients and professionals and to act within a common legal framework. They want to be involved all along the process of CTs, starting from recruiting the participant, though information activities and disseminating the results. Reinforcing the role of POs will increase the level of trust towards the research sector. Indeed, both of the surveys conducted by EPF highlighted that parents tend to mistrust based on their lack of - or limited access to - information.
This second survey stressed an additional aspect: the role of the media in creating fallacious perceptions. General media tends to emphasise the importance of natural remedies, creating a negative perception of traditional medicine. This can bias the approach of parents considering involving their children in CTs. At the same time, scientific magazines with more accurate information are not so accessible at the public level. POs can thus be expected to reduce information gaps at the level of parents involved in CTs through education and training, but also at public media level, by pursuing and reinforcing their activities of information dissemination.
The experience of CTs staff
1. Focus group with German clinical research staff: RESPECT conducted a focus group with German researchers and clinicians to explore their concerns about the difficulty of recruiting children to studies that imply some risk for the child.
2. Focus group with Swedish clinical research staff (diabetes): RESPECT ran a focus group with Swedish nurses involved in a diabetes vaccine CT. The discussion material consisted of patient statements drawn from our earlier literature search and case studies indicating why they had participated in a CT, as well as additional statements suggested from the literature review indicating why a patient might refuse to participate.
3. Focus group with Swedish clinical research staff (cystic fibrosis): The clinical staff reported that, because CF is a chronic disorder, they build up a strong relationship with their patients over many years, which makes it easier to encourage them to be in a CT. The team staff reported low dropout rates in their trials, probably because of this strong relationship. They discussed how much harder this would be if they were dealing with, for example, cancer patients who would have recently got a diagnosis and be coming to a clinic where the staff didn't know them. It would be hard to establish trust quickly and their acute condition would make them less willing. Parents would find it tough to make such a decision in this situation.
Interviews and survey with paediatricians
This part of the RESPECT project aimed to explore how paediatricians approach the task of recruiting children and their parents to CTs.
Data collection took place in Nov-Dec 2009. There were four interviews with professors of paediatrics in Sweden, Italy, Germany and the Netherlands. The same questions in the form of a survey were distributed to paediatricians in Slovenia and we received ten responses. These respondents had considerable experience of CTs, recruiting on average 85 participants each (ranging from 10 to 300).
Families' motivations to accept
The expectation of better treatment motivates both the families and the paediatrician. Indeed, the paediatricians commonly reported that they emphasise the extra monitoring and potentially better treatment when encouraging families to participate. As a consequence, a comment was made that some parents may feel that they will not get full and appropriate treatment unless they agree to participate in the CT. The personal relationship with the doctor was considered to have an impact, with the child and the parents wanting to follow the doctor's wishes. In return, the paediatricians were concerned to reduce inconvenience & pain as far as possible and wanted protocols to minimise the number of blood tests the child would undergo.
Explaining CTs
When asked about what families understand about clinical research and whether it is hard to explain about the CT, many of the paediatricians reported that the parents' level of knowledge varies and that children understand even less and can be inattentive. These paediatricians gave vastly different responses when asked how old a child needs to be to give their assent (ranging from 4 to 18 years of age). Particularly problematic are situations where the parent will consent, but the child will not give assent (especially if he or she is rather small); children do not see the necessity for the study.
On the question of explaining risks and benefits, they stressed the importance of being honest, as you would with your own child, with explanations appropriate to the child's age. Listening and responding to the family's questions was considered important. These subtle skills are not available in the ethics committee guidelines.
Payback to participants
More than half of the respondents reported that they give the family information on the results of the study, but in several cases this was only on request. One paediatrician suggested that knowledge is something they could offer when encouraging participation, because the interested parents and children will learn about the research by participating. Interestingly, some of the respondents mentioned that patients would like to see more gratitude from the staff or the sponsor, probably reinforced by token gestures (gifts or treats, such as a meal) for the children.
Recruiting patients: discussion with experienced paediatricians
In January 2010, we held a seminar with the senior paediatricians among the RESPECT project partners, to find out more about their experience in relation to the interview and survey responses we had gathered from other paediatricians.
Barriers to participation
The parents who are most resistant to invitations to enter their child in CTs are the ones for whom the existing treatment is working well and the CT concerns testing different doses or oral versus intravenous administration. They do not want to change anything, so recruitment will be a problem and the CTs will probably have to reduce the sample size required for significance (as they do now for orphan diseases). It may even be necessary to recruit from more countries. Often around half of those asked to participate will refuse. One suggestion was that there should be campaigns (appeals) to the public to raise awareness of CTs and increase the likelihood of participation.
If the parents have no established relationship with the doctor (for example, a mother approached when she has just delivered), only about 20 % will agree to let their child participate. They are usually the more educated mothers who feel research is important and personal benefit to the child is likely. The other 80 % do often come round to the idea later and it is very rare for families to withdraw once they are in a trial. If their child has a chronic disease, they are more likely to participate for altruistic reasons; they feel that they will see reciprocal benefit in the long run.
In the case of chronic diseases, the clinicians already know the patients and may ask them to be in many trials. Indeed, they avoid inviting new patients to participate and wait until they know them better. In any case they would always contact the patient's primary care physician for background information (medical history and also previous compliance to their medical regime). The patient's physician may have little experience of randomised CTs or alternatively have been involved in many trials before. He or she may be asked to join someone else's CT as a satellite trial centre but an alternative is to send the patient(s) to the main trial centre instead. This may be better for the patient in terms of expert monitoring. It means that the patient effectively receives a second opinion on their diagnosis and prognosis, which the primary physician may see as a benefit or (possibly) a threat.
Exclusion
Immigrants tend not to get included in CTs. There is an assumption they will not understand the instructions because of low education, but this may be an assumption by medical staff. We need to be more inclusive and provide cultural mediation, not just translation. There is a European Commission project called European standards on confidentiality and privacy in healthcare among vulnerable patient populations (EuroSOCAP) that is producing guidelines on addressing patients in their strengths instead of focusing on their weaknesses.
In the case of HIV (in which the child contracts their condition from their mother), it has been observed that some mothers refuse to let their child participate because they themselves had a bad experience (such as a rash) with the drug and don't want the child to risk this. Since adherence is important, the clinician will not enter these patients in a CT of a drug they are unlikely to take.
Spontaneous requests
If the patient is on a standard drug and it is not helping, the parents are glad to try something new. In fact, they consistently ask spontaneously to be included in any trials that may be started, especially if their child has a fatal disease. Many parents spontaneously seek information about their child's condition on the internet.
Patients who are more empowered will want to find a CT that suits them. It is possible - at least in United States of America (USA) and Sweden - to respond to an advert in the press or radio recruiting CT participants, but in other countries, these spontaneous applications by patients may not be allowed.
Conclusions from survey and interviews
These responses raise the question of whether the existing good clinical practice guidelines are enough. Just ticking informed consent checklists may not be a guarantee of true informed consent. We cannot be sure whether parents and children have really understood what they are being asked to do or whether they consent instead because they trust the doctor, the nurse or the researcher to do what is in their best interests. This leaves families in a vulnerable position.
There is a risk that some adults (among both clinicians and parents) do not consider the child's opinion to be valid and do not communicate directly with the child. It is important to gain the family's respect and trust by being honest - as one would with one's own child; the clinical staff must give and take feedback before, during and after the trial.
The responses highlight the importance of clinical staff respecting their patients' needs in order to increase willingness and motivation to participate in a CT. It is important to listen to the family's concerns; wherever possible, the clinical staff should strive to reduce distress for the child and keep inconvenience for the family to a minimum.
Physicians are in a unique position to inform trial sponsors about the child's unmet medical needs and to influence which trials are conducted, but it was not clear whether they use this influence; however, they do sometimes emphasise to sponsors that they prefer to avoid too many blood tests on their young patients.
It is important to ensure that families understand the need for research and are respected for their valuable contribution to CTs; randomisation must be clearly explained and the clinical staff must show appreciation, acknowledging that the child is a 'medical hero'.
The experience of CT networks
CT networks: involvement of paediatric patients and their parents
Survey findings
Our consultation shows that only three out of the eight paediatric CT (PCT) networks participating in the survey systematically involve patients and/or POs in their clinical research. Two of these networks are 'disease oriented' and fall in a very specific 'rare diseases' category, while the third (MCRN) is a 'generic' network facilitating the development of medicines that are both safe and effective in the treatment of children.
CVBF-TEDDY highlights the fact that the direct participation of patients in the planning stage of the clinical research depends on the type of study and in particular on the investigated disease: if there is a strong PO (as in the case of thalassaemia and cystic fibrosis), it is more likely that their input is sought from the early stages of the research.
Recruitment is usually carried out within the network's members and/or participating centres; if the number of patients recruited through the network is not sufficient, specialists and/or POs (in the case of rare diseases) are contacted; only occasionally the CT is publicised through advertisements.
Feedback is systematically given only by PENTA, while usually it is encouraged, but not always attainable. The amount of information given to patients depends on the sponsor, but usually data relate only to the general outcome of the trials, while personal information is typically not given.
Examples of best practice are provided by Finpedmed, PENTA and MCRN.
1. Finpedmed developed a national template for providing information on a CT to paediatric patients of all age groups and templates for informed consent in all age groups. They have also developed picture cards to use when providing information on a CT for children.
2. PENTA established youth groups that providing feedback on their HIV infectious status and their medical and social care.
3. MCRN encourages the active involvement of young people and families in the design and delivery of CTs via the MCRN young person's advisory group, or topic specific focus groups.
Conclusions
The European paediatric regulation posed the legal basis for the development of the 'European network of existing national and European networks, investigators and centres with specific expertise in the performance of studies in the paediatric population'. The European Medicines Agency (EMA) was appointed the responsibility to set up such a network and in May 2010, the recognition criteria requirements to become member of the network were agreed on by participants from 38 national research networks and CT centres and the EMA.
CT networks interested in joining the network were invited to complete a self-assessment form (to be updated annually). A total of 33 networks submitted self-assessment forms to the EMA: 18 are now officially members of the European network of paediatric research (Enpr-EMA); one was, at the time of writing, undergoing clarification and 14 do not qualify for membership.
Recognition criteria for self-assessment
The self-assessment form contained the following six criteria that networks should fulfil to be recognised as a member of the Enpr-EMA, namely research experience and ability; network organisation and processes; scientific competencies and capacity to provide expert advice; quality management; training and educational capacity to build competences; and public involvement.
Conclusions
It is sometimes assumed that involving families in making the informed consent material clearer is the closest patients, families and/or POs can get to involvement in the design of CTs, but this report shows that much greater involvement is possible and is already practised by these organisations to some extent.
Public involvement is required by European Authorities.
The inclusion of patients, parents or their organisations in the Networks' activities as one of the qualifying criteria for membership in Enpr-EMA is just one of many examples within the EMA, that includes POs representatives in their various Committees and working groups.
The fact that those networks not qualifying as members of Enpr-EMA are also those that apparently have weaker links with patients is a fact that should not be taken lightly, especially if compared with the very different approach employed by Enpr-EMA member networks that on the other hand more systematically involve patients and their representatives. Making patients able to have a direct input in the design and execution of the trial, as well as in the prioritisation of needs, will motivate their participation. In addition, a closer cooperation between researchers and children and/or their representatives as active research partners enriches the understanding of the medical condition and the outcomes.
There are many initiatives aimed at promoting and encouraging patient and public involvement in clinical research and many examples on how to make these initiatives successful: PENTA, MCRN UK, ECFS-CTN. These networks prove that the involvement of the public does work.
The experience of ethics committees
Survey on the involvement of European ethics committees in paediatric research
The CT-Directive introduced a number of measures to harmonise the ethical review of CTs and facilitate clinical research. It required member states (MS) to legally establish ethics committees, including obligations and specifications, formal procedures and timelines, composition and competencies. Specific provisions were also adopted for reviewing CT protocols including children. However, due to the nature and legal force of a Directive, MS had some flexibility in implementing its provisions in their national legislation. Thus, ethical review procedures and the amount and quality of publicly available information vary significantly among European countries.
To evaluate the impact of the new European paediatric regulatory framework on the activities of ethics committees charged with reviewing paediatric research protocols, the TEDDY network of excellence and RESPECT set up an inventory of ethics committees existing in Europe and conducted a survey among them on their approach to paediatric trials.
Impact of the European paediatric regulation and European ethical recommendations
Overall, ethical committees (ECs) recognised, as possible effects of the new European paediatric regulatory framework, the increased involvement of children in clinical research and, thus, an increase in the number of medicines tailored for children, as well as better-designed paediatric trials and more multicentre paediatric clinical studies.
When asked about the influences of the new regulatory framework on their work, around two-thirds of the 73 responding ECs reported no impact or low impact from the paediatric regulation or the European ethical recommendations and under 10 % acknowledged a high impact.
This low impact was particularly true of ECs operating in EU-15 MS (Belgium, France, Germany, Ireland, Italy, Luxembourg, Portugal, Spain, Sweden and the Netherlands). In contrast, one-third of ECs in new EU MS (Cyprus, Czech Republic, Estonia, Latvia, Malta, Poland) declared a high impact of the paediatric regulation and most acknowledged either high or sufficient impact of the European ethical recommendations. These data suggest that ECs in the new EU MS are more actively involved in efforts for integration and harmonisation towards EU research and health norms and systems than EU-15 ethics committees.
The major influences recognised by ECs were: the creation of new rules for reviewing paediatric protocols and sometimes changes in the EC organisation; increased quality and number of paediatric protocols and especially the increased time needed to review these protocols. Lesser effects included increased attention to paediatric protocols; increased facility to carry out paediatric trials; and the necessity to specify ethical requirements. It was also underlined that it is difficult to adapt information to parents and children in accordance with the new requirements.
Main issues to be dealt with by ECs
Looking at the opinions of ECs on the major issues to be dealt with under the regulatory framework, about half of our sample identified the increased need for additional expertise to evaluate paediatric protocols and for measures to minimize pain, distress and fear of children. It was stressed that there is still a lack of knowledge regarding the risks and burdens that are acceptable for children in different age groups. Complexity in evaluating inclusion/exclusion criteria, risk/benefit balance and consent/assent procedures were also highlighted as main concerns.
Training and networking for ECs
Only 30 % percent of the 73 respondents indicated that they had participated in initiatives in the field of paediatric research and those who did mainly took part in conferences and, to a lesser extent, training activities. Moreover, a significant number of ethics committees operating in Europe showed interest in initiatives related to paediatric research, preferring means such as training at national and local level and networking among ECs. Debates and conferences (at the national level) and educational initiatives supported by European institutions were also of interest. Three-quarters of those ethics committees interested in networking belong to the EU-15, while the remainder are established in new MS (Cyprus, Czech Republic, Estonia, Latvia, Malta, Poland).
Conclusions
This survey demonstrated that there is a lack of knowledge of the European paediatric regulatory framework among ethics committees and that their awareness of ethical issues related to paediatric research is limited, reflecting their low level of involvement in paediatric research, especially in terms of training, education and other similar activities.
Given that ECs are one of the most important actors in guaranteeing the safety, rights and well-being of children involved in clinical research, it is of primary importance to increase their competence and their involvement in paediatric research and to promote the implementation of the European ethical recommendations at the local level. In this context, training and education in the field of ethics of paediatric clinical research should be an important objective.
Networking may be a fundamental tool to enhance collaboration and experiences and information exchange. It should be particularly important to promote these initiatives in the new MS, where the number of CTs is increasing.
One possible relevant result of networking could be the development of a comprehensive guide practically addressing paediatric ethical issues in accordance with all the relevant international and European ethical and legal sources. This guide, chaired at the EMA level, should address all those specific ethical issues related to paediatrics: information/authorisation-assent process, paediatric expertise of ethics committees in charge of reviewing paediatric protocols (including training and education of the members of the ECs), use of placebo, compensation for damage, as well as other specific aspects to be considered in reviewing paediatric protocols.
Swedish central ethical review board interview
Background: the structure of Swedish ethics committees
In Sweden there is one central ethical review board, which was founded in 2004 and six regional boards, which are situated at the Universities of Gothenburg, Linköping, Lund, Umeå and Uppsala and at the Karolinska Institute in Stockholm.
These are independent authorities, divided into two or more sections that make decisions on behalf of the regional board. Each section is headed by a chairperson who is a judge or has been one. The sections have ten members with scientific qualifications and five members representing the general public. It is important that every application should be processed by members who have sufficient expert knowledge. The scientific members are therefore highly qualified. All members and their substitutes are appointed by the government. Each of the sections is expected to have 10 to 12 meetings annually.
Within each section, a scientific secretary is appointed from among the scientific members. Together with the chairperson of the sections, the scientific secretaries are responsible for processing cases and dealing with them.
Conclusions
This interview confirmed the picture of a lack of knowledge among ethics committees of the European paediatric regulatory framework. It also reflects the closed structure of ethics committees and their reluctance to include parties who could contribute to their work.
The experience of the pharmaceutical industry
RESPECT conducted four phone interviews with senior managers in the area of protocol feasibility and patient enrolment within both small and large multinational pharmaceutical companies.
It should be pointed out that pharma companies lacking a strong patient focus were less likely to agree to be interviewed and it was generally difficult to make contact even with companies who appeared to have admirable practices, judging from the materials they made available in the public domain, because of standard corporate policies about protecting company-confidential information.
Our interviews gave a snapshot of pharma companies with a commitment to facilitating patients' participation in paediatric CTs. They are aware of the importance of keeping families informed and reducing the burden for the child, but they still have to improve their contacts with POs, for example in allowing them to contribute by reviewing the CT protocols.
Main conclusions from the RESPECT findings
Many of the parents we interviewed saw the trial as a way to get the latest and best medicine for their child (thus misunderstanding the principle of equipoise that is fundamental to CTs). Both children and parents were surprised to find that some of the procedures were painful.
Paediatricians reported that parents did not always understand the difference between CTs and regular treatment. They felt that many parents did not see the importance of medical research and did not always have an altruistic attitude. Longer-term participants are no longer able to identify differences between their normal treatment and the CT.
When faced with the decision to participate, families identified a need to trust the doctors and nurses as a motivation for participation. However, other parents saw themselves as research partners in the trial and wanted to feel that their input was valued, although they did not always feel that their contribution was appreciated sufficiently. They wanted to receive the study results but several paediatricians confirmed that they do not inform parents about the results unless specifically asked.
Several POs reported that they were ill equipped to give input on which trials and which outcomes have the highest priority for their members. This is something that could be improved through surveys of their members as a basis for contact with pharma companies.
We found good examples of trials where patients felt empowered to make valuable contributions. We also found POs giving input into trial design and protocols, helping to define outcome measures and to recruit trial participants, as well as pharma companies making their trial results accessible to all via their website. It is important to ensure that families understand the need for research and are respected for their valuable contribution to the improved safety of medicines for children.
Potential impact:
The project has contributed towards the impacts listed in the original work programme. The major impact of this project has been on the promotion of CTs for the development of innovative medicines to improve child health and treat paediatric diseases. We have identified areas of cooperation between different partners in the CTs landscape which will help to make CTs more effective and thus encourage greater innovation and industry development.
This project has created the possibility of cooperation wherein greater participation in CTs will be achieved through identifying the RESPECT tools and mechanisms required to empower patients and promote a debate on the benefits of biotechnology. The project has advanced our understanding of how to more efficiently promote good clinical practice in CTs research through various debates between different actors within this field.
The lack of participants in CTs research, especially children, has been a major bottleneck to the development of new medicines. Improved competitiveness of the European-based pharmaceutical industry through releasing this bottleneck has been addressed at various meetings.
The project has lead to the development of a set of norms and standards for CTs, which in its turn will lead to the accelerated development of new or improved medicines for child diseases. Moreover, the project has had an impact on improving links between research organisations, patient representatives and industry.
Account has been taken of other national or international research activities in this field through the broad networking with the partners. The RESPECT partnership has been able to take advantage of the close link to other networks within the European framework and this has ensured that all our discussions have been included in the debate on needs of the paediatric CTs participants. Working closely with other network projects and with our approach to a broad membership of the dissemination workshop in Brussels which was held at the end of the project has ensured the high impact of the project.
Through close contacts with POs and through the projects web page the project has encouraged an informed societal debate on the benefits and risk of participation and the eventual benefits of an improved biotechnology industry.
The educational packages and decision aid which have been developed are made available through our dissemination activities and through the web site. These will encourage further research and development in this area and ultimately greater participation of people in CTs research. The project has taken a European (rather than a national or local) approach which has made it possible for the project to address the concerns of patient needs in a research are that is increasingly European. It is only at the European level that legislation can be effective in changing the way that CTs will be carried out. It is only at the European level that requirements can be set for industry and we can develop a broad based strong CTs landscape which will promote innovative medicine development in Europe. This will form the basis upon which the industry will grow. This is particularly true for the small to medium sized businesses who will, due to the need to minimise risk capital, want to stay within the European framework.
The positive impact of information sharing
According to the recent Eurobarometer survey in 2006, one in two Europeans believe that biotechnology will improve their quality of life. The survey showed widespread support for medical and industrial applications of biotechnology therefore the situation has been ripe for the promotion of increased participation in CTs. The positive impact of the RESPECT project will be seen as the debate on the benefits and risks of participation between different stakeholders will identify the benefits and risk of CTs participation.
All centres have been strongly encouraged to work in partnership with local and national research groups and companies involved in CT research. This liaison has enhanced an important consultative role for several partners.
The methodology and requirements for generating empowerment have been identified and the RESPECT project has developed professional materials such as a book, decision aid and training packages that will ensure that individuals and those professionals who work with CTs have the opportunity to utilise the projects findings. A European dissemination conference was hosted by the project to ensure dissemination to policy makers, service providers and service users. In addition, the production of training packages, together with the RESPECT website has provided a wider dissemination of the issues.
The results of the RESPECT project have been published in the literature and will continue to be the basis of further publications. RESPECT will maintain a website after the project has ended so that it acts as a reference database for others working in the same field. Maximum use has been made of Community/International Clinical Congresses to discuss the outcomes of the study and to disseminate the results as widely as possible to all within the European CTs landscape. All partners have contributed throughout Europe to the dissemination information about the project and its results at conferences and seminars.
Contribution to standards
The aim of the project has been that the results will contribute to international standards of good clinical practice in CTs with children. This will be further encouraged through our publications.
Contributions to policy development
The project results have, via the dissemination activities, fed into the development of policy in this area. As the impact of the new regulations of the testing of medicines for children takes effect policy will also need to be developed. The project has been timely in that the results are able to inform and influence the development of those policies throughout Europe. Comments were sent to the rapporteur at the EC concerning the concept paper for public consultation on the revision of the CTs directive 2001/20/EC.
This project has contributed to the coordination of high quality research by going beyond the current state of knowledge and identifying the needs and motivations of children and their families when participating in CTs. The project has drawn together different actors in an open debate on the how Europe can be more encouraging to the participation of children in CTs. The project workshops have been open to everyone in the field and this has meant that greater networking could be possible. Together with the partners in the project who represent both the research side and the patients side of the debate a stronger and more fruitful coordination with different actors having an equal role has been realised. We believe that the project will continue to benefit the work programme by being able to support the health theme across a number of areas. The results will be directly implemented by the clinical partners. This will have a snowball effect as the benefits of the approach become evident. The results will be applicable to all medications and all medical conditions. The results will also be transferable to adult CTs as the relevance of the needs approach and empowerment of the patient will be applicable to the adult patient groups.
Project website: http://www.patientneeds.eu