Clinical trials in neonates: How to optimise informed consent and decision making? A European Delphi survey of parent representatives and clinicians
Clinical trials in neonates: How to optimise informed consent and decision making? A European Delphi survey of parent representatives and clinicians
Virginia Neyro 0 1
ValeÂ ry Elie 0 1
Nicole Thiele 1
Evelyne Jacqz-Aigrain 0 1
0 Department of Paediatric Pharmacology and Pharmacogenetics, Assistance Publique des H oÃpitaux de Paris, Robert DebreÂ Hospital , Paris , France , 2 Doctoral School MTCI ± Paris Descartes University , Paris , France , 3 European Foundation for the Care of Newborn Infants, EFCNI, Munich, Germany, 4 INSERM Clinical Investigations Center CIC1426, Robert DebreÂ Hospital , Paris , France , 5 EA08 ± Paris Diderot University , Paris , France
1 Editor: Bridget Young, University of Liverpool , UNITED KINGDOM
Parental consent for the participation of their neonate in neonatal research is influenced by the quality of the information delivered and the interaction between parents and investigators. Failure to provide important information may lead to difficulties in the decision making process of parents. This Delphi survey aims to establish a consensus between parent representatives of neonatal associations and healthcare professionals concerning the information deemed essential by both parties in order to improve the recruitment of neonates into clinical trials.
Data Availability Statement: All relevant data are
within the paper.
Funding: This work was supported by the
European Union Seventh Framework Programme
FP7/2007-2013 under grant agreement no. 261060
(Global Research in Paediatrics Network - GRiP) to
EJA. The funder had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
This study was conducted in Europe among parent representatives and healthcare
professionals. In this 3-phase study, 96 items were defined by the Scientific Committee (CS),
composed of 11 clinicians (from 8 countries) and 1 parent representative of the European
network of neonatal associations. Then the Committee of Experts (CE) composed of 16
clinicians were matched by country with 16 national parent representatives and evaluated
these items in two rounds. The importance of each item was evaluated by each member of
the CE on a scale between 1 and 9 based on their personal experience.
Fifty eight items reached the second and final level of consensus. In contrast to clinicians,
parent representatives preferred to be informed about the study by the physician in charge
of their child. They also favoured additional support during the informed consent process
and stated that both parents need to agree and sign.
The set of 58 items on which parents and clinicians reached consensus will be helpful to
healthcare professionals seeking parental consent for the inclusion of a neonate in a clinical
trial. Providing parents with information about the trial by the investigator in the presence of
the patient's neonatologist, developing closer contacts with parents and informing them of
the available support by parents associations may be helpful for parents.
For years children have been "therapeutic orphans" and denied the benefits of clinical research,
most prescribed drugs being unlicensed and/or off-label medicines for this particular
population. Since 2007, the European Paediatric Regulation stimulates systematic paediatric drug
evaluations through Paediatric Investigation Plans. It aims to improve the development and
facilitate accessibility of medicinal products for use in the paediatric population, including in
]. Clinical trials remain the golden standard for drug evaluation. Whilst in the
adult population patients need to provide their consent to participate in a trial, the situation is
quite different for neonates, where parents take the responsibility for their child's enrolment.
Obtaining parental consent relies on providing the necessary information to help parents to
take an informed decision. This exchange of information between investigators and parents is
a serious challenge for clinicians [
]. Failure to provide important information may lead to
difficulties in the decision-making process of parents.
Asking for parental consent in neonatology is complex and several studies have focused on
elements that may facilitate communication. The understanding of the randomisation process
by parents is particularly important in order to help them decide whether their child should be
included in the trial [
Thus, the optimisation of the quality of information provided to parents is important to
help them understand the scientific and ethical rationale of the trial.
Priorities regarding the information that should be provided may differ between parents
and investigators [
]. For example, parents prioritise explanations about the current clinical
status of their child or the characteristics of the study itself [
]. Understanding the point of
view of both parents and clinicians on the type of information to be provided during the
informed consent process may result in an increased acceptance and a decrease of withdrawal
Therefore, this Delphi survey [7±10] aimed to establish a consensus between representatives
of parents of neonates and healthcare professionals to identify criteria considered important in
the informed consent process.
This study was evaluated by the ethics committee at Robert DebreÂ Hospital. All participants
agreed to participate in this survey by responding positively to an invitation after being
informed about the objectives and organisation of the study.
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Purpose, rationale and study design
The purpose of this study was to establish a consensus between parent representatives and
healthcare professionals on the information to be provided during the process of obtaining
informed consent for the inclusion of a neonate in clinical research.
The rationale for this study was based on the currently very limited literature providing
guidance and the observation that the needs of parents and investigators during the informed
consent process may differ [
Using the Delphi methodology this European study was conducted among parent
representatives of newborns and healthcare professionals.
The Delphi method consults experts on a specific topic aiming to reach a consensus. It is
organised in various rounds during which experts are asked to express their opinion on
specific items. Following each round the group's responses to each item are provided to all
participants. Each individual is then encouraged to reconsider and where appropriate change their
reply in the next Delphi round, taking into consideration the view of the group. This process is
repeated until a consensus is reached.
This survey included a Scientific Committee (SC) and a Committee of Experts (CE). Experts
were people with sufficient practical, political, legal or administrative knowledge of the subject.
The impartiality, independence and absence of conflict of interest of participating experts
were ensured by the Scientific Committee during the selection process for the Committee of
Scientific CommitteeÐSC. The Scientific CommitteeÐSC (analysts) was responsible for
the organisation of the Delphi survey. It selected the members of the Committee of Experts,
drafted the successive versions of the questionnaires and analysed and summarised the results
after each round. The SC was composed of specialists in the field of neonatology and clinical
trials. Members of the SC were selected based on their scientific expertise, years of experience
and their number of publications. Furthermore, the SC included the chair of the first
panEuropean organisation representing the interests of premature babies and their families
(European Foundation for the Care of Newborn Infants—EFCNI). The EFCNI has established a
network of stakeholders collaborating to improve long-term health of neonates by reducing the
rate of preterm births and ensuring optimal treatment, care and support during the neonatal
Committee of ExpertsÐCE. The Committee of ExpertsÐCE (experts) was composed of
healthcare professionals (paediatricians, neonatologists, obstetricians, pharmacologists,
researchers, study coordinators, specialists in medical ethics and members of ethics
committees) and parents representing the different national organisations of parents of premature
babies, collaborating with the EFCNI.
These being themselves parents of neonates born prematurely, they have therefore coped
with the complications of such situation. Given their position in the organisations, they
transmit discussions, opinions, thoughts and interests of the parents they represent, as well as their
own. They were proposed by the central EFCNI chair, Nicole Thiele, because they were
considered competent to answer the Delphi questionnaire based on their own experience.
Selection of experts and representativeness. The identification and selection of experts
was based on criteria recommended by the Delphi methodology [7±12]. The criteria included
their willingness and availability to participate in the survey, as well as their qualifications,
publications and experience in the field. Further criteria were their interest in the subject matter,
3 / 18
their impartiality, independence and absence of conflict of interest. Finally, the diversity of
their points of view, geographical location and their scientific expertise were considered.
To ensure representativeness of the responses and to take into account potential country
specific particularities a parent representative from the same country was selected for each
healthcare professional contributing to the CE.
Questionnaire preparation and selection of preliminary items
The first version of the questionnaire was drafted after a review of the relevant literature. The
search was conducted using PubMed and included the following keywords: informed consent,
parents or parental, investigators, clinical trials or paediatric/neonatal trials, children or
neonates. Based on this literature review, 92 items, reported as being important during the
informed consent process, were included in the first version of the questionnaire and sent to
the SC for review.
The SC was asked to keep, remove or modify them as needed, including the possibility to
add new items between March and May 2016.
This review resulted in a final questionnaire of 96 items to be evaluated by the CE. None of
the members of the CE requested adding further items.
These 96 items were organised into seven headings: I. Information provided to the parents
(10 items); II. The information disclosure process (19 items); III. The decision making process
(17 items); IV. Criteria that may influence the decision making process (29 items); V. Criteria
concerning the informed consent (8 items); VI. Criteria that may encourage a positive decision
to the inclusion of the newborn in the study (8 items); VII. Reasons for a negative answer to
participation from the parents (5 items).
To facilitate data collection, the questionnaire was developed using an online platform. Data
was collected anonymously and kept confidential. Communication not relating to the content
of the questionnaire occurred via e-mail.
This Delphi survey was conducted in accordance with the recommendations for the
assessment of healthcare quality [
]. Its methodology was consistent with the literature in terms of
the number of rounds, number of experts and cut-off levels for consensus. However, the
methods of Delphi studies do vary as noted in a systematic review conducted by Boulkedid and
] and the ªThe RAND/UCLA Appropriateness Method User's Manualº [
on currently used cut-off values, we used a scoring of 1±9 for the importance of the different
items with median scores of 7±9 being considered high enough to reach consensus [
As described in the Delphi methodology, all 96 items were rated twice by the CE (Fig 1). In
each round the experts (CE) were asked to rate the items on a scale from 1 to 9 according to
the level of importance, based on their personal experience and beliefs: 1 being ªnot important,
not true, should be dropped as an item to consider, totally disagreeº and 9 being ªextremely
important, obligatory, true, must be an item to consider, totally agreeº.
First round. Round one of the survey was conducted between August 2016 and January
2017. Items with a median score of 7 or higher and rated in the top tertile (7 to 9) by at least
65% of the CE were kept for the second round (first level of consensus). In addition,
demographic information on the participants was collected at this occasion (field of expertise, place
of employment, function, and knowledge and experience regarding clinical trials).
Second round. The second round was performed between February and May 2017. For
each item, the CE members were informed of the rating they had provided in the first round as
well as a summary of the rating of the CE group for each item (median, percentage of rating in
4 / 18
Fig 1. Overall organisation of the Delphi process.
the top tertile and frequency distribution). Finally, items with a median score of 7 or higher
and rated 7 or higher by at least 75% of the CE were kept for the final list of items (second level
In addition, items and comments not included in the final consensus such as diverging
opinions between parent representatives and healthcare professionals were examined and
The organisers of this survey invited 25 professionals with several years of experience to
become members of the Scientific Committee based on their expertise in the fields of
paediatrics, neonatology or clinical research. Five refused to participate due to lack of time or because
they considered having insufficient knowledge of the subject matter. A further six did not
respond to the request. Two other professionals accepted initially but withdrew in the end.
Thus, 12/25 (48.0%) experts from 9 countries composed the Scientific Committee. The group
consisted of 11 healthcare professionals and 1 parent representative.
For the Committee of Experts, 26 healthcare professionals were contacted to participate, 10
of which did not respond. Twenty-two national parent representatives were contacted with the
help of the EFCNI, 6 of which did not respond. Therefore the Committee of Experts consisted
of 16/26 (61.5%) healthcare professionals and 16/22 (72.7%) parent representatives from 10
countries in Europe.
Eleven out of 16 parent representatives (68.8%) declared that they had knowledge of clinical
research and 5 (31.3%) had their own child involved in a study. As for clinicians, 15 (93.8%)
had previous experience in neonatal trials and 14 (87.5%) had experience in providing
information in the context of obtaining informed consent from parents.
Table 1 shows the characteristics of the panellists including their area of expertise.
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Function and main area of expertise, n (%)
Number of children, median [range]
Number of sick neonates, median [range]
Involvement / experience in providing information to parents of neonates for their inclusion into a
clinical trial, n (%)
Involvement of their newborn in a clinical trial, n (%)
Responses to questions asked in the questionnaire
Are clinical trials in neonates difficult to conduct? YES n (%)
Are neonatal trials required? YES n (%)
Should they be conducted in "specialized" Neonatal Care Units?YES n (%)
Data concerning 11 physicians
Based on 15 answers
PLOS ONE | https://doi.org/10.1371/journal.pone.0198097
6 / 18
Fig 2. Flowchart of the results of the Delphi survey.
All 32 experts (100%) participated in both the first and second round of the Delphi process.
Based on the first level of consensus 63 of 96 items (65.6%) were retained (Fig 2). Thirty-three
items (34.4%) were excluded: 18 (18.8%) did not reach a median rating of 7 or above and 15
items (15.6%) were rated in the top tertile but by fewer than 65% of the panellists.
The results of the Delphi survey are presented in Table 2. This includes the median score
for each item as well as the percentage of respondents rating the item 7 or higher.
In the second round, the CE was asked to re-evaluate the 63 items kept following the first
Items rated with a median score of 7 or higher and 75% of the respondents rating them in
the top tertile were considered for the final consensus. A total of 58 items (92.1%) of the 63
submitted reached this second level of consensus. Five items (7.9%) were excluded.
The 58 items reaching consensus after the two rounds of the Delphi are presented in Table 3.
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N A T P P P L P
1 Information disclosure sheet and informed consent form should be included in one unique document.
4 All items listed in the information leaflet should be presented orally.
6 The information sheet should be consistent with the oral information given.
7 It is important that the parents have the possibility to read the information sheet before taking the decision.
8 It is important that the parents keep the information sheet and reread it whenever they wish during the trial.
9 Parents who decide to withdraw should be asked whether they give their consent to the use of already collected
10 Parents who decide to withdraw should be asked if data collected as part of their routine care can still be
collected even after withdrawal (i.e. some parents might want to withdraw from an invasive protocol but still
accept ongoing collection of data).
SECTION 2: THE INFORMATION DISCLOSURE PROCESS
A. Staff responsible for delivery of the information
11 The information can be delivered by the physician in charge of the neonate.
16 All study personnel who provided the information should be able to answer any additional questions or doubts
that the parents should have, at any time during the study.
B. How to provide information?
18 Every reasonable effort should be made so that the information about the study is provided face to face to both
parents at the same time.
22 Every reasonable effort should be made so that the information about the study is provided to the other parent,
even if it needs to be done by telephone, video, etc.
24 Information about the study should be provided in the native language of the patient's parents.
25 Information about the study should be provided in the presence of a qualified translator, so that it is provided in
the native language of the patient's parents.
27 Information about the study should be provided in words adapted to the level of comprehension of each of the
patient's parents, as NO-technical as practical, so that it remains understandable to them.
28 Identical information has to be provided to both parents.
29 In the context of a neonatal urgent trial or one starting immediately after birth, information can be disclosed to
the parents before birth, even if this may result in parental additional stress.
SECTION 3: THE DECISION MAKING PROCESS
A. When the information is given to parents, please rate some of the identified difficulties
B. What help/support is important in the decision making process
35 A full confidence in the medical team taking care of the neonate, available to discuss all aspects of the protocol
and help with the decision making, might be important in the decision making process.
39 Discussions / exchanges with parents who were previously involved in neonatal trials, might be important in the
decision making process.
C. Deadline for positive or negative response to participation in the trial
42 Time provided to the parents to make a decision usually depends on the context of the study.
43 Time provided to the parents to make a decision may influence it in a positive or negative way.
44 Time required by the parents to take a decision should be respected, considering that if they cannot decide
within a time line that is reasonable for the researcher or needed for the study, the patient will not be included.
SECTION 4: CRITERIA THAT MAY INFLUENCE THE DECISION MAKING PROCESS
A. The neonatal health / situation
47 The neonatal health/situation may have a an
impact on the decision to accept participation.
48 A serious health condition.
E. What do you think are parents expectations regarding
the investigators' skills/competencies?
69 Clinical trials expertise.
70 Expertise in the medical area where the trial will be
49 The severity/gravity of the prognostic.
50 Limited expected survival.
71 Communication skills.
72 Honesty and sincerity.
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73 Transparency of information.
60 Need to transfer the patient to another facility.
78 Both parents can sign the written consent separately.
61 Need to extend hospitalisation (even if it is for a SECTION 6: CRITERIA THAT MAY ENCOURAGE A
limited duration. . .). POSITIVE DECISION TO THE INCLUSION OF THE
NEWBORN IN THE STUDY
C. Criteria concerning parents during the decision 84 An altruistic motivation driven by the existence of
making process collective benefits.
63 Stress caused by the disclosure of information.
85 The possibility to contribute to progress in medicine and
64 Ability to understand the information received
and to reason clearly.
87 Promoting a better understanding of one's own child's
D. Decision making process
88 Potential direct and personal benefits for the neonate.
66 Difficulty and importance of making the best
decision for the patient.
89 Potential increase of the chance of survival, in the
absence of alternatives.
67 The parents can feel as being entirely
responsible for the decision.
68 The professional in charge of information
disclosure may influence the decision of the
90 Lack of validated existing treatment.
91 Potential indirect benefits to other neonates with similar
94 The involvement of the regular care team (physician, nurse. . .) is important to create a climate of trust with the
95 The mother is not always available (in the maternity ward), her separation from the neonate may encourage a
96 It is challenging to add the stress of a trial to the burden of a sick neonate.
After the evaluation of the CE, all of the 7 initial headings were maintained: I. Information
provided to the parents (7/10 items); II. The information disclosure process (9/19 items); III.
The decision making process (5/17 items); IV. Criteria that may influence the decision making
process (24/29 items); V. Criteria concerning the informed consent (3/8 items); VI. Criteria
that may encourage a positive decision to the inclusion of the newborn in the study (7/8
items); VII. Reasons for a negative answer to participation from the parents (3/5 items).
Differences between clinicians and parent representatives
During the first round parent representatives and healthcare professional agreed on the
assessment of 65 out of 96 items (level of agreement: 67.7%). However, 31 items (32.3%) were
rated differently between the two groups. Parent representatives rated 25 items as important
(median score 7 or higher and rated 7±9 by at least 65% of respondents) but healthcare
professionals did not agree. In turn 6 items were rated as important by healthcare professionals but
parent representatives did not agree.
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Selected items were distributed differently among parent representatives and healthcare
professionals. Only 48 items (50.0%) reached the first level of consensus when rated by the
healthcare professionals, whereas 67 (69.8%) would have been retained by parent
representatives (Fig 2).
In the second round, healthcare professionals and parent representatives agreed on the
evaluation of 52 out of 63 items (level of agreement: 82.5%). The remaining 11 items (17.5%) were
rated differently by the two groups of experts. Parent representatives assessed 10 items as
important but healthcare professionals did not agree. One item was considered important by
healthcare professionals but parent representatives did not agree.
Similar to the differences observed in the first round, parent representatives and healthcare
professionals differed on the number of items they selected as being important in the second
round. Parent representatives considered 61 out of the 63 items (96.8%) as being important
whilst healthcare professionals chose 52 items (82.5%).
The present Delphi survey was conducted in order to obtain a consensus between parent
representatives and healthcare professionals on the information disclosure process to parents for
the inclusion of neonates in clinical trials.
The inclusion of subjects in neonatal research has proved to be a problematic process.
Obtaining a valid informed consent for the inclusion of a newborn in a clinical trial depends
on the proxy consent given by the parents [
]. In general, consent for participation in clinical
research is considered valid if the following three conditions have been fulfilled: information,
comprehension and voluntariness [
]. However for a sick neonate, all three conditions may
be difficult to assess [
]. First of all, the provision of complete and accurate information about
the trial to parents depends mostly on the training and skills of the staff communicating with
the parents. Effective communication during the informed consent process is not only
important in the context of clinical trials in neonates but in any trial including oncology trials
]. Furthermore, parental comprehension may be compromised by their level of medical
understanding, the urgency of the trial, emotional distress and many other factors such as the
quality of the written and oral information provided . Finally, the free will of a parental
decision may not be easy to assess in situations where parents are vulnerable and they might
be at risk of being influenced by someone else's opinions or beliefs.
Informed consent in neonatology is the result of a conglomerate of circumstances both
relative to the clinicians in charge of the study and the subjects expected to give authorization for
the newborn's participation. Basic elements to be included in a consent form, such as the
purpose and procedures of the study, anticipated risks or potential benefits are described in the
Guidelines for Good Clinical Practice (GCP) [
], and later confirmed using the Delphi
method to develop a guideline for clinical trial protocol content [
Nevertheless, the process of providing information in order to help with the decision of
whether or not to participate in a clinical trial remains to be explored further. Understanding
the reasons resulting in an affirmative or negative parental decision to include their newborn
in a trial may also help improve the informed consent process.
A multidisciplinary panel of 32 experts including both healthcare professionals in the field
of neonatal/paediatric clinical research, as well as parent representatives evaluated a total of 96
items divided in 7 sections concerning this complex informed consent process.
The questionnaire was organised in a way that allowed exploring what information needs
to be delivered to parents and by whom (sections 1 and 2); what the decision making process
may represent for them (section 3); which criteria may influence their decision in a positive or
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negative way (headings 4, 6 and 7); and finally, their expectations concerning the signature of
the informed consent (section 5).
Parent representatives and healthcare professionals agreed on the rating of most items
concerning the delivery of information. However, on some items, the two groups shared different
points of view which appeared to be influenced by their personal or professional experience.
The information presented orally should be as complete as possible, consistent with the
items included in the information leaflet and be provided in the native language of the parents,
which may require the help of a qualified translator. As described in the GCP guideline, the
words used to describe the trial and its characteristics should be non-technical and
understandable for lay people [
]. Information should be provided to both parents at the same
time. However, clinicians agreed, in both Delphi rounds, that information could be given to
only one of the parent if the other was not available. However, they noted that the other parent
should be informed as soon as possible. Parent representatives did not agree with the
suggestion that only one parent could be informed. This resulted in the removal of this item at the
end of the first round. Parent representatives were also in favour of having a third person
present during the informed consent process, such as a family member or their family doctor.
However, healthcare professionals did not share this view.
Furthermore, parent representatives expected information on the trial to be provided by
the physician in charge of the child. In contrast, healthcare professionals considered, in
agreement with article 4.8.5 of the ICH Guideline for GCP, that information should be given by a
professional not in charge of the patient such as the investigator or another physician informed
of the protocol [
When considering the timing for the informed consent process parent representatives
initially considered that information should not be given before the child is born. This view
included trials beginning immediately after birth and emergency treatments. This observation
contradicted the suggestions made by parents in a survey conducted in a Canadian neonatal
intensive care unit (NICU). When asked about improvements to be made in the recruitment
process, parents recommended that information about the study should be provided before
birth to allow sufficient time for reflection [
]. The time the parents have to make a decision
may vary between studies. Insufficient time adds considerable stress to parents who find
themselves already in a difficult situation. It is also a factor that may influence the decision making
process negatively and could make the consent provided not valid [
representatives responding to this Delphi survey requested that the minimum duration of time provided
to make a decision should be predetermined in the protocol and established by an ethics
committee. Currently available guidelines present insufficient information about the appropriate
time point and how much reflection time should be allowed for seeking parental consent.
Studies about continuous consent have suggested the usefulness of providing information to
research participants at different stages of a trial in order to help clinicians obtain optimal
informed consent [
Surprisingly, the members of the Committee of Experts considered none of the 5 items
describing potential difficulties encountered by the parents when information about the trial
is provided to them as being important. Neither healthcare professionals nor parent
representatives thought that misunderstanding the purpose of the study and its potential impact could
influence the decision making process. Most of the experts consulted for this survey had
sufficient knowledge about clinical research therefore they might be less aware of the challenges
faced by parents unfamiliar with clinical trials. However, different studies seeking the points of
view of parents showed that understanding of the characteristics of a clinical trial was not
always sufficient [
]. Some parents showed no or insufficient recollection of giving
13 / 18
consent for participation in a research project. Trial related procedures and treatments were
considered by some parents as part of routine medical care . Interestingly, even if the level
of understanding by parents was not complete, they showed satisfaction about the information
given by the investigators [
]. This may explain why a lack of understanding of certain
medical terms or specific criteria does not necessarily compromise the whole decision making
Parent representatives and healthcare professionals disagreed on items of support that may
be useful for the parents. Parent representatives considered seeking themselves information
about the study to be helpful, as well as having support from friends and members of the
family. They strongly agreed that contact with specialised parents associations or psychological
assistance might be important during the decision making process. However, it has to be
noted that these parents are members of such specialised parents associations. By contrast,
healthcare professionals did not consider these items to influence the decision making process
of parents. However, a previous Delphi survey reported the importance of having additional
support, such as the possibility to exchange with parents previously involved in neonatal
]. As expected, trusting the members of the medical team responsible for the care
of the newborn is considered essential by parents facilitating the decision making process [
The whole CE agreed that reliability and availability of the clinicians were important. Other
skills parent representatives expected from investigators are clinical research expertise as well
as knowledge of the medical speciality concerned by the study. Parents trust the information
provided if investigators have good communication skills and are honest, sincere and clear
when informing about a trial. The availability of professionals at any time of the decision
making process is considered fundamental by parents.
Many different criteria can influence the decision making process and parents being more
or less stressed and vulnerable during the informed consent process. The health status of the
newborn including the seriousness of the condition and prognosis can influence the attitude
of parents. Parent representatives attached more importance than professionals, in terms of
item rating, to the possibility of being aware of a neonatal disease prior to birth giving them
more time to think about treatment strategies or potential inclusion in a research.
Both groups of experts agreed in both rounds that some study characteristics such as
invasive procedures and the disruption of family life if the child is transferred to another facility
may influence the decision making process. The need to prolong the duration of
hospitalisation, as well as the duration of trial participation was considered important by all experts.
Parent representatives considered it important that parents facing a request to include their
newborn into a clinical trial should have the opportunity to talk to parents who have been in a
similar situation. In particular, considering that having a neonate who is critically ill is already
very stressful for parents. However, clinicians did not agree with this view.
This survey confirms that the responsibility of taking the decision to include their newborn
in clinical research can be overwhelming for parents. Parents felt strongly about the
importance of making the best decision for their child and considered being fully responsible for that
choice. They may feel that they do not have a full understanding of all the factors to be
considered and their implications whilst being the only ones who can decide what is best for their
]. In both rounds all of the experts agreed that the professional responsible for
providing the information to the parents may influence the opinion of the parents about having
their child included into the trial.
Final consensus was obtained for nearly all proposed items relating to reasons that might
encourage a positive decision of including a neonate into a clinical trial. Of course, the
possibilities of increasing the chances of survival or having other direct benefits for the neonate are
14 / 18
a strong motivation for the acceptance to enter a child into a trial. Similarly, a proposal to
study a drug is more easily accepted when there is a lack of established treatments. Potential
direct or indirect benefits for other neonates in similar situations, as well as the contribution to
the understanding of the child's disease also played a role in encouraging acceptance of the
inclusion of the newborn [
]. Parent representatives strongly agreed that contributing to the
progress in medicine and neonatal research encouraged a positive decision, whereas clinicians
considered that it would not motivate parents. Interestingly, all healthcare professionals agreed
that personal and direct benefits for the patient would be the most important point for parents
to include their child into a trial. However, during the first round, this was certainly not the
most important item for parent representatives.
Parents who agree to have their child participate in a clinical trial need to sign the informed
consent form provided by the investigator. All experts agreed that both parents should be
present at the time of signing the informed consent form. However, clinicians rated this lower
than parent representatives. Both signatures are required to officially begin participation of the
neonate to the trial, but these can be obtained separately, as reported by our Committee of
Experts. Whilst clinicians considered it acceptable that just one parent signs, parent
representatives felt that both parents need to sign even in countries where legally only one signature is
considered sufficient. Despite efforts made to standardise paediatric clinical research in
Europe, requirements for obtaining consent depend on the different national laws and
regulations and therefore vary widely between countries [
]. The members of our panel of Experts
come from 10 different European countries. Six of them (Hungary, Finland, Ireland, Poland,
Spain and United Kingdom) require only one parent to sign. The other 4 (Belgium, France,
Italy and the Netherlands) demand, in most situations, both signatures at some point in the
This is, to our knowledge, the first European consensus obtained among healthcare
professionals and parent representatives on the information disclosure process and request of written
consent for the inclusion of neonates into a clinical trial. As expected, this Delphi survey has
revealed various important issues to be taken into consideration in neonatal research with
some of the items reaching final consensus and others showing differences between parent
representatives and physicians.
It should be pointed out, as a limitation, that only 5 out of the 16 parent representatives in
the Committee of Experts had themselves experienced the inclusion of their newborn into a
clinical trial. Nevertheless, all of them having had preterm infants, these parents had
experienced the difficulties linked to the hospitalisation of a neonate. Seeking their advice on the
informed consent process is therefore justified. The outcome of the survey might have been
different if members of the Committee of Experts would have requested to comment or
modify the survey items prior to the first round. The final consensus obtained here concerned the
items reaching the pre-established level of agreement for all members of the Committee of
Experts but it does not necessarily reflect the individual views of parent representatives or
In conclusion, the news that their newborn is seriously ill can be devastating and stressful
for parents. For some trials beginning immediately after birth, the time parents have for
making a decision about consent is often very limited and the weight of the decision weighs on
them. Every effort should be made by the investigators in charge of the study, as well as the
medical team, to improve the circumstances of providing information during the informed
consent process. It is important that the expectations of parents are well understood and that
support and help is provided to facilitate a truly informed consent process.
15 / 18
We would like to express our gratitude to all the members of the Scientific Committee,
especially Nicole Thiele, Vice Chair of the Executive Board of the EFCNI, for her precious help in
selecting and contacting the parents; and the Committee of Experts, both the professionals and
the parents, for their important contribution to the survey.
Healthcare professionals: Karel Allegaert (Neonatal Intensive Care Unit University Hospitals
Leuven, Leuven, Belgium), Imti Choonara (Derbyshire Children's Hospital, Derby, United
Kingdom), Roland Gerull (Inselspital, University Hospital Bern, Bern, Switzerland), MartÂõn
Iriondo (Sant Joan de DeÂu Hospital, Barcelona, Spain), Evelyne Jacqz-Aigrain (Robert DebreÂ
Hospital, Paris, France), Thierry Lacaze-Masmonteil (Children Hospital of Eastern Ontario,
Calgary, Canada), Jean-Paul Langhendries (CHC Saint-Vincent, Rocourt, Belgium), MarÂõa
Cruz LoÂpez (Cruces University Hospital, Bilbao, Spain), Stuart MacLeod (BC Children's
Hospital Research Institute, Vancouver, Canada), Mike Sharland (St George's University
Hospitals NHS Foundation Trust, London, United Kingdom), John Van Den Anker (Children's
National Medical Center, Washington, USA).
Parent representative: Nicole Thiele (European Foundation for the Care of Newborn
InfantsÐEFCNI, Munich, Germany).
Committee of Experts
Healthcare professionals: Yannick Aujard (Robert DebreÂ Hospital, Paris, France), Eugene
Dempsey (University Maternity Hospital, Cork, Ireland), RubeÂn GarcÂõa (University Hospital
Salamanca, Salamanca, Spain), Viviana Gianuzzi ('Gianni Benzi' Pharmacological Research
Foundation, Bari, Italy), Sabrina Goudjil (CHU Amiens-Picardie, Amiens, France), Emmanuel
Lopez (CHRU Clocheville, Tours, France), Pierre Maton (CHC Saint-Vincent, Rocourt,
Belgium), Marek Migdal (Children's Memorial Health Institute, Warsaw, Poland), Eleanor
Molloy (National Maternity Hospital, Dublin, Ireland), Edit Muhari-Stark (Medicine for Children
Research Network, Budapest, Hungary), JoseÂ Luis Neyro (Cruces University Hospital, Bilbao,
Spain), Helen Sammons (Derbyshire Children's Hospital, Derby, United Kingdom), MikloÂs
SzaboÂ (Semmelweis University Faculty of Medicine, Budapest, Hungary), Outi Tammela
(Tampere University Hospital, Tampere, Finland), Dick Tibboel (Sophia Children's Hospital,
Rotterdam, The Netherlands), Wannes Van Hoof (Bioethics Institute Ghent, Ghent, Belgium).
Parent representatives: Ana Alos (Prematura, Barcelona, Spain), Livia Bonnard (Melletted a
helyem Egyesulet, Budapest, Hungary), Mandy Daly (Irish Neonatal Health Alliance, Dublin,
Ireland), Vincent Desdoit (SOS preÂma, Boulogne-Billancourt, France), Dagmar Frenssen
(Vlaamse Vereniging voor Ouders van Couveusekinderen (VVOC), Leuven, Belgium),
Stephen Griffiths (Bliss, London, United Kingdom), Catherine Hubert (SOS PreÂma, Bordeaux,
France), Heli Kauppinen (Kevyt (MLL Meilahden yhdistys ry), Helsinki, Finland), Tomasz
Makaruk (Fundacja Wczesniak RodziceÐRodzicom, Warsaw, Poland), Jane Moffat (Piccino
Picciò, Florence, Italy), Kinga Morvay (Melletted a helyem Egyesulet, Budapest, Hungary),
Elaine NÂõ BhraonaÂin (Irish Neonatal Health Alliance, Dublin, Ireland), Audrey Reynaud (SOS
PreÂma, Nice, France), Gert Van Steenbrugge (Vereniging van Ouders van Couveusekinderen
(VOC), Leidschendam, The Netherlands), Yannic Verhaest (Vlaamse Vereniging voor Ouders
van Couveusekinderen (VVOC), Leuven, Belgium), MoÂnica VÂõrchez (Prematura, Madrid,
16 / 18
Conceptualization: Nicole Thiele, Evelyne Jacqz-Aigrain.
Funding acquisition: Evelyne Jacqz-Aigrain.
Methodology: Virginia Neyro, ValeÂry Elie, Evelyne Jacqz-Aigrain.
Resources: Evelyne Jacqz-Aigrain.
Supervision: Virginia Neyro, ValeÂry Elie, Evelyne Jacqz-Aigrain.
Writing ± original draft: Virginia Neyro, ValeÂry Elie.
Writing ± review & editing: Virginia Neyro, ValeÂry Elie, Nicole Thiele, Evelyne
17 / 18
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