Introduction

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 neonates [1]. 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 [2]. 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 [3,4].

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 [5]. For example, parents prioritise explanations about the current clinical status of their child or the characteristics of the study itself [6]. 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 from studies.

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.

Methods

Procedure

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 [10]. 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 colleagues [10] and the “The RAND/UCLA Appropriateness Method User's Manual” [13]. Based 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 [10,14,15].

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 “not important, not true, should be dropped as an item to consider, totally disagree” and 9 being “extremely important, obligatory, true, must be an item to consider, totally agree”.

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Fig 1. Overall organisation of the Delphi process.

https://doi.org/10.1371/journal.pone.0198097.g001

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 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 of consensus).

In addition, items and comments not included in the final consensus such as diverging opinions between parent representatives and healthcare professionals were examined and summarised.

Results

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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Table 1. Characteristics of the Delphi panellists.

https://doi.org/10.1371/journal.pone.0198097.t001

All 32 experts (100%) participated in both the first and second round of the Delphi process.

First round

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.

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Fig 2. Flowchart of the results of the Delphi survey.

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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.

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Table 2. Results of the Delphi survey.

https://doi.org/10.1371/journal.pone.0198097.t002

Final consensus

The 58 items reaching consensus after the two rounds of the Delphi are presented in Table 3.

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Table 3. Final consensus of the Delphi survey.

https://doi.org/10.1371/journal.pone.0198097.t003

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).

Discussion

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 [16]. In general, consent for participation in clinical research is considered valid if the following three conditions have been fulfilled: information, comprehension and voluntariness [17]. However for a sick neonate, all three conditions may be difficult to assess [18]. 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 [19,20]. 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 [19]. 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) [21], and later confirmed using the Delphi method to develop a guideline for clinical trial protocol content [22].

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 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 [21]. 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 [21].

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 [23]. 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 [24,25]. Parent 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[26]. 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 [27].

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 [28,29]. Some parents showed no or insufficient recollection of giving consent for participation in a research project. Trial related procedures and treatments were considered by some parents as part of routine medical care [30]. Interestingly, even if the level of understanding by parents was not complete, they showed satisfaction about the information given by the investigators [29]. This may explain why a lack of understanding of certain medical terms or specific criteria does not necessarily compromise the whole decision making process.

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 research [31]. 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 [32]. 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 child [33,34]. 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 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 [35]. 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 [36]. 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 process [37].

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 clinicians.

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.

Acknowledgments

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.