Michela Masoero

	The Informed Consent Form (ICF) and Assent Form (AF) documents play an essential role in pediatric clinical trials. The successful enrolment, compliance and retention of pediatric patients rely on the quality of these documents as well as the quality of the consent and assent process. While the majority of the EU countries have amended their legislation in line with the requirements of the European Directive for clinical trials, 2001/20/EC, significant differences with respect to local legislative requirements for pediatrics ICF and AF remain. This current lack of harmonization in the ICF and AF documents is also apparent when analyzing the results of the 2012 EUCROF survey, published in 

 in February 2014. In this survey, several difficulties in respect to pediatric ICF and AF were observed. Many European countries do not have a specific template and requirements for the pediatric ICF and AF and there is also a difference in the age as to when it becomes mandatory to obtain a child´s signature.

	The Pediatric Working Group of EUCROF has launched an initiative with the final goal to achieve the standardization of generic ICF and AF templates within the EU countries. This initiative was launched to improve the quality of the consent and assent process with an objective to enhance the quality of the trial, which will at the end facilitate an improved process for development of pediatric drugs. As a first step in 2014, a pan-European survey was performed, regarding national legislation and requirements governing ICF and AF documents. Some non-EU countries were also included.

	A survey questionnaire was developed consisting of 21 questions summarizing the most important information with respect to the local legislative requirements and guidelines for ICF and AF.

	The survey was distributed electronically through the EUCROF network. The regulatory country specialists from different contract research organizations (CROs) and members of EUCROF within local jurisdictions collected and summarized the feedback. The local regulatory specialists collected the information from the official websites and other official documents published by competent authorities and leading ethics committees (ECs) frequently involved in pediatric clinical trials. Whenever needed, a direct communication with the corresponding authority was established and specific question was clarified. The received data were centrally compiled and analyzed by EUCROF PWG members.

	The following 27 European countries, including Norway, Turkey and Switzerland, but excluding Croatia, Luxemburg and Malta, have provided information about their local requirements for obtaining informed consent and assent in pediatric clinical trials.

	Survey results confirmed that general requirements for the Patient Information Sheet and the Consent/AF (not age-specific) to be used in pediatric populations are common within the European countries. The content is in the line with GCP E6 4.8 requirements in all countries. The information must be written in the native language of the child and adolescent in order for them to fully understand the clinical trial, and the information provided should be directed to the child/adolescent. In general, the information should be provided by a medical doctor experienced in pediatric clinical trials, who should ensure that the pediatric patient/healthy volunteer understands the meaning of the trial and has received answers to all his/her questions. However, only a few national legislations specify that the person handling the ICF and the Assent process should be a certified medical doctor, such as, for example, the German legislation. 

	The AF for a pediatric patient/healthy volunteer (subject) participating in a clinical trial is necessary, though in most countries there is no a legal requirement that the form has to be signed by a child, or at least not until up to a certain age. The clinical trial and the AF must have prior approval from national competent authorities/ECs. From a legal point of view, in some countries, the signed consent form by parent(s) is sufficient to enroll a pediatric subject into the clinical trial.

	• As presented in Table 2, the AF is a requirement in 12 out of 27 of the European countries in which data were collected. 

	• It is observed that there is a significant age difference, as to when an AF is considered a legal/EC/IRB requirement. For example:

		In Lithuania, an AF should be presented to children from the age of 5 years. 

		The Czech Republic does not have a clear statement in their legislation, though it is assumed to be from 6 years of age. 

		In Turkey, Romania, Austria and Greece, it is from 6-8 years. In Switzerland, and in the remaining countries, the age ranges from 11 years to 16 years, whereas the Netherlands state 12 years. 

		In Finland and Sweden, parental consent is no longer needed for children who are 15 years or older. The subjects can sign the ICF if they fully understand the concept and implications of the trial, per the judgement of the investigator. 

	• There are no specified laws regarding AF in Slovakia, Hungary, Spain and Germany. In Italy, an AF adapted to the subject’s age is required by law. 

		Austria, Estonia, Turkey, Romania, Lithuania, and Greece require a signature from the age of 5-8 years. 

		In the Netherlands, a signature is required from 12 years; in Bulgaria from 14 years; in Spain from 15 years; and in the remaining countries who participated in the survey, the signature is foreseen from 15-16 years of age. 

		Germany has nothing specified in the law in this regard, though it is recommended to have a signature from the age of 7. 

		In Portugal, a signature is not mandatory but it is common practice to obtain it. 

		Czech Republic and Latvia state that the child should sign an AF, when he or she is able to write. 

		Ireland encourages a child´s signature, to give a child a sense of autonomy and respect of ethical considerations.

Specific guidelines and requirements and age classification

	In general, two AFs should be used: one for children up to 11 years and one from adolescents from 12 to less than 18 years. The local legislation is not always clear and, in fact, some ECs in certain country require two AFs for the lower children´s age group (i.e., one for 5-8 and one for 9-11 years). 

	While in all countries there is a requirement for the AF, in some countries outside of Europe there is no requirement for the child to sign it. Our survey shows the specifics of European national legislation and although it looks quite varied, the majority of countries require a pediatric signature from a certain age.

Informed Consent Form for parents/legal guardians:

	• The legal guardian(s) have the same rights as the parent(s). There is no information available on this matter for Finland, Norway and Sweden. For Portugal, this is not defined. 

	• In some European countries the signature of both parents is required, while in other European countries, one parent’s signature is sufficient. 

		In the case of divorced/separated parents, only the parent with custody is required to sign the ICF. 

		There is no information available on this matter for Finland, Norway and Sweden. 

		In Lithuania, according to Article 7 of the Law on Ethics of Biomedical Research (“Protection of Vulnerable Persons”), if the subject is a minor, consent to undertake a biomedical research shall be given by both parents or by the legally acceptable representatives of the minor and the children’s rights protection agency of a district or a city.

	Rewards for participation in clinical trials are either prohibited or not allowed, whether it is for the child or the parents. Compensation is permitted only to cover travel expenses or losses related to absence from work. In general, the specific rules are defined by the local ECs and not by the competent authorities, and any compensation should be approved by the ECs.

	Although, in general, the requirements for the ICF and AFs in pediatric clinical trials within European countries are similar and in accordance with the ICH GCP, our survey indicated that in some aspects there is a difference within individual countries, and in some cases there is a lack of clarity in national legislations. The observed differences are not critical, but still make pediatric clinical trials performed across different European countries more challenging. There is a clear need for further harmonization of the documents and consent/assent process requirements, as this would facilitate the conduct of clinical trials in children and would increase the quality of trials, thus contributing to the development of better medicines for children.

	The Pediatric Working Group of EUCROF will continue to update information around the current state of the ICF and AFs and related procedures. The final goal is to develop standardized general templates for the ICF and AF that can be used in pediatric clinical trials within the European Union as a starting point. For this initiative, a collaboration with further stakeholders such as Enpr-EMA, the national ECs and the competent authorities is strongly recommended.

, with EUCROF and SynteractHCR, Germany; 

, with EUCROF and Chiltern, Netherlands; 

, with EUCROF and Appletree-CIG Group AG, CH; 

, with EUCROF and Zeincro Hellas, Greece; 

Articles

The Pediatric Working Group of EUCROF launched an initiative to achieve standardization of generic Informed Consent Form and Assent Form templates within European countries. The differences are noted based on a prior survey.

European Pediatric Informed Consent and AF: Current Status of Country Requirements

Editor's Note: An abridged version of this story appeared in the February/March issue. You can find that version 

 which entered into force in January 2007, requires that any new marketing authorization applications of medicines for the general population (new active ingredients, new indications, formulations and routes of administration) should include studies carried out in the Pediatric population in compliance with an agreed Pediatric Investigation Plan (PIP).

The Pediatric Working Group (PWG) of the European CRO Federation (EUCROF) conducted a follow-up survey on the status of pediatric clinical trials in Europe after publication of initial data in 2010 (

, February 2010, 46-53). The new survey, collecting information from pediatricians, pharmaceutical/biotech companies and Contract Research Organizations (CROs), has confirmed the challenging operational, ethical and methodological aspects encountered in pediatric trials, the need to improve parents’ and patients’ motivation and patient retention in the studies. Support is felt to be needed by pediatricians to overcome the practical difficulties of the trial organization. On the other hand, pediatricians and sponsoring companies would benefit from training on the specific regulatory, ethical, and methodological implications of the pediatric clinical development. Synergies should be implemented between all parties to give a better chance for the development of new drugs for children.

Since January 2007 the European “Pediatric Regulation”1 has fostered ethical research and ensured appropriate authorization and information on medicines for children. The challenging nature of pediatric clinical research requires competence for a full appreciation of the evolving clinical trial methodology in this setting and a deep knowledge of the specific regulatory requirements. The Pediatric Working Group of the European CRO Federation (EUCROF-PWG) first analyzed the status of pediatric clinical research in Europe by conducting a survey in 2007.

 The results revealed a relatively low number of ongoing pediatric trials while it was expected that the European Pediatric Regulation would stimulate more pediatric research. Based on the information in the public European clinical trials database (EudraCT), the number of authorized pediatric trials, which were part of an agreed Pediatric Investigation Plan (PIP) was 70 in 2011, representing 19% of all pediatric studies.

 According to the recent report of the Pediatric Medicines Section that evaluated research activities during 2011 and that was submitted to the European Medicines Agency (EMA), pharmaceutical companies seem to be meeting their clinical trial obligations in view of a marketing authorization, however, some major deviations from the rules set by the Regulation were observed, in particular, often poorly justified late submissions of PIPs/waiver applications and slow progress of the clinical trial plan.

 Nonetheless, further research incentives are provided by the EMA through the EU Framework Program by funding studies for off-patent medicinal products, in view of the submission of a Pediatric Use Marketing Authorization (PUMA). This program will hopefully give further impulse to pediatric research, but will also amplify the need of quality improvement in pediatric clinical research.

Another survey performed by the EUCROF-PWG in 2009 aimed to determine the main difficulties and constraints in pediatric research among European CROs, pharmaceutical companies and Institutional Review Boards/Ethics Committees (ECs).

 Most respondents reported to have conducted less than five clinical trials in children over the last three years. From the responses, it was evident that there was space for improvement in the application of an appropriate methodology, but also a need for support. In particular, support is needed for a better understanding of how to design pediatric clinical trials, how to select appropriate and validated end-points, how to write good Patient Information Sheets (Informed Consent and Assent Form), and for ECs, how to gain more experience in the process of pediatric study protocol assessment.

A follow-up survey was launched in 2011 by the EUCROF-PWG to evaluate the current situation relating to pediatric clinical studies and to determine whether the concerned stakeholders had gained more experience in pediatric clinical research. The analysis involved the number of studies conducted, the difficulties encountered in conducting clinical research with children, the perception of the need for external support and the experience/competence of the ECs. This last survey was addressed to pediatricians, pharmaceutical/biotech industry, and CROs in Europe in order to collect different points of view and provide a framework for the assessment of the status of pediatric clinical research. The present article reports the results of this last survey, and identifies current strengths and weaknesses in pediatric clinical research and the evolutionary pattern of the approach to pediatric drug development since the introduction of the European Pediatric Regulation. 

Between May 2011 and March 2012, the EUCROF-PWG prepared and distributed a questionnaire to 350 pharmaceutical/biotech companies, CROs, and pediatricians in various European countries (Belgium, Czech Republic, France, Germany, Greece, Hungary, Italy, Lithuania, the Netherlands, Spain, and UK). Data from the returned questionnaires were entered into a project database, using a mask to manually encode the answers. After the first complete data entry, a second data entry of randomly selected questionnaires was made and a comparison of the two databases was performed for data quality control. 

All respondents who stated that they had been involved in pediatric clinical research have been considered for the statistical analyses. Qualitative variables have been described by means of absolute and relative frequency distribution. Questionnaires with missing values have not been excluded, and for each analysis the number of items with missing data has been reported. 
  
The analyses have been performed using SAS software (SAS Institute, Cary, NC, USA).

The questionnaire was composed of four sections:

An introductory part with information on the respondent: sponsoring pharmaceutical company (with ranking of the enterprise in the local market based on annual turnover), CRO (with ranking information on the number of employees), pediatrician (with indication on where the clinical activity was being performed, i.e.at an academic/research institution, general hospital, private practice or within a pediatric network).

The second (main) section proposed thirteen questions on the following items: awareness of the Pediatric Regulation 1901/2006/EC; impact of the Pediatric Regulation on the pharmaceutical development; impact of the Pediatric Regulation on therapeutic needs, on development of innovative drugs, on increasing profitability of existing dugs and on cost impact in public health; information on the extent of experience in clinical research with children (number and characteristics of studies conducted, by phase of development and indication); main difficulties encountered in conducting clinical research with children; tasks with a need for external support; pediatric experience/competence of the involved ECs ; success in obtaining ECs approval; usefulness of training focused on issues related to pediatric clinical trials (and which topic of highest interest); opinion on the availability of information on pediatric clinical trials; best source for acquisition of information on pediatric clinical trials; reasons for insufficient progress of clinical trials in children; concerns for the future of pediatric clinical research.

The third section was specific for pediatricians with three aspects: question on the percentage of their last 20 prescriptions of drugs having a pediatric approved indication; possible solutions to improve their therapeutic decisions; a comment on whether the pediatric medical community made sufficient collaborative efforts toward the development of pediatric drugs.

The fourth section was specific for the industry with two questions on actual submissions of PIPs or applications for PUMA by the company, and a comment on whether the pharmaceutical industry made sufficient efforts for the development of pediatric drugs. 

Of the 350 questionnaires sent out (60% of these to CROs/pharma companies; 40% to pediatricians), 58 were completed and returned. The response rate was 13% from companies and 20% from pediatricians. Respondents who declared not to be involved in clinical research in pediatrics did not provide information so that they were not considered for statistical analysis (N=2).

Out of 56 respondents evaluated, 29 (51.8%) were pediatricians (mostly from academic institutions or general hospitals), 15 (26.8%) were CROs (mostly country affiliates), and 12 (21.4%) were pharmaceutical or biotech enterprises (mostly ranking within the top 10 in the local markets). The data analyses have been conducted separately for pediatricians (N=29) and sponsors/CROs together (identified hereafter as “companies”: N=27). Sponsors and CROs data were pooled because they have similar roles in carrying out clinical trials. Results are reported as percentages of responses in each category analyzed.

Knowledge of the Pediatric Regulation 1901/2006/EC

The knowledge of the Pediatric Regulation 1901/2006/EC is widespread among respondents (93% within companies; 83% among pediatricians), thanks to a direct involvement in pediatric studies which represent a main source for familiarization with the regulation (Table 1). Although about 70% of companies and pediatricians believe that the Pediatric Regulation might eventually lead to favorable effects on the therapeutic needs of the pediatric population, it is surprising that there is moderate expectation of the Pediatric Regulation to impact effectively on the availability of new medicines authorized for children, and even less regarding the availability of new indications, new formulations, or an impact on off-patent drugs (Table 2).

It is noteworthy that the awareness of the likely increase of costs in public health, which can be an effect of the increased research activities and related costs, is evidently low (10% to 11 %).

Experience in clinical research with children

63% of companies reported to have started no more than two pediatric studies in the past three years (including 25% of companies reporting no studies at all). Data reported by pediatricians were biased by a high rate on non-responders to this question (56%); the remaining 44% of pediatricians was evenly distributed among the categories of none, one or two, three to five, more than five studies in the last three years (Table 3).

Because clinical research plays a dominant role in the final availability of new drugs, we have investigated the level of experience in the various phases of the clinical development. Good or fairly good experience (relating to a four-level scale: good—fairly good—poor—none) has been reported especially in Phase II and Phase III studies (Figure 1), while Phase I has been identified as the area with less experience. Observational studies were mostly performed by pediatricians, as non-commercial sponsors of such studies.

Large experience was reported by both companies and pediatricians mainly in oncology, vaccines and hematology.

Difficulties in performing clinical research with children

Due to the peculiar characteristics of the pediatric population, clinical research with children may encounter special difficulties related to protocol development, ethical aspects, and practical issues. Such aspects were investigated with a series of defined items rated as to the difficulty in carrying out the specific task (very difficult—difficult—easy—very easy) or the need for external support (definitely—possibly—unlikely—not at all). Figure 2 shows responses cumulating “very difficult or difficult” ratings, and Figure 3 responses on “definite—possible need of support.” Both practical and methodological aspects appear to be critical while designing and carrying out a study for children. Obtaining the parents’ understanding and their consent is reported as critical and represents a frequent difficulty for the inclusion of a sufficient number of subjects in the studies, the latter being regarded as the most challenging aspect in performing clinical trials in children (74% and 59% for companies and pediatricians, respectively). An additional complication is represented by the collection of biological samples, especially when these are frequent or invasive.

Methodological aspects are more frequently a matter of concern for the sponsoring companies/CROs, probably because they have regulatory relevance and involve the specific responsibility of the sponsor. Such critical methodological aspects include: getting appropriate patient-derived data, setting validated endpoints that are appropriate for pediatric aims, and sample size calculation. Conversely, monitoring and obtaining resources dedicated to the trials, or writing a correct informed consent sheet, are felt to be major hurdles for pediatricians (Figure 2). 

When exploring the need of support, as a consequence of the difficulties highlighted, pediatricians seem to be more demanding all across the wide array of items proposed, as listed in Figure 3, especially for the practical and administrative aspects encountered in the conduct of a clinical trial, such as “obtaining appropriate insurance,” “receiving IRB approval,” or having support for the trial monitoring. These outcomes reflect the difference between investigators and sponsors in terms of structure and organization, whereby the availability of dedicated and experienced staff in the companies allows clearance of such problems in a relatively easy way. The recruitment problem is the only matter of concern that is evenly distributed between companies and pediatricians (as expressed by 44% and 52% for companies and pediatrician, respectively).

Ethical aspects are critical especially in child-related research; therefore, the interaction with ECs should be easy and supported by mutual trust. In general, the competence of ECs is highly appreciated.

In most cases, the protocol submitted for ethical review is eventually approved by the consulted ECs, however, with substantial comments from the ECs in 63% and 45% of instances, as respectively reported by companies and pediatricians, out of the following choices: approval always/in most instances—substantial/frequent comments—frequent rejection.  This outcome indicates that the preparation of the study documentation is sometimes insufficient or unclear for a smooth ethics review.

Availability of information and educational activities

In order to improve the awareness of the various aspects of pediatric research, and also to increase skills and competence in the practical aspects of trial conduct, the participation in specific training was felt as useful by most respondents. In fact, the educational support currently available through publications, seminars, trainings, guidelines has been considered inadequate (“less than needed” or “inadequate” amount of information, out of a three-level scale: adequate—less than needed—inadequate) by 74% of companies and 69% of pediatricians. Topics most welcomed by companies were those related to compliance issues, enrollment/retention of patients, informed consent preparation and general ethical issues, pharmacokinetics, European Pediatric Regulation, and PIP preparation. Pediatricians have raised the need for advancement in informed consent preparation and general ethical issues, regulatory affairs, and European Pediatric Regulation (Figure 4).

The best source of information on pediatric clinical trials is felt to be represented by the internet with dedicated web pages or special events (seminars, workshops, or specific training sessions) (Figure 5).

Main constraints with clinical trials in children 

According to companies’ respondents, clinical trials in children find constraints mainly because of recruitment issues (44%), legislative or administrative issues (30%), and difficulty in obtaining parental consent (30%). Different opinions were expressed by pediatricians, who were most worried by difficulties in obtaining ethics approval (38%), low interest of sponsors (38%), and low financial investments (31%) (Figure 6).

The future of pediatric clinical research

Like the issues described by companies as the main reasons for the slow development of pediatric research, similar concerns are also expected for the future, as being related to recruitment (63%), parental consent (41%), legislation or administrative hurdles (26%), low interest of sponsors (26%), and slow implementation of legislation (22%) (Figure 7). Parental consent and recruitment are less frequently mentioned by pediatricians (14% and 10%, respectively), while legislation or administrative hurdles, low interest of sponsors, and slow improvement of legislation are felt by pediatricians as more critical (66%, 55%, and 31%, respectively).

The majority of the pediatricians (72%) believe that their therapeutic choices would be better supported by personal updates, based on easy access to the available literature, acquisition of experts’ opinion, or participation in congresses. Personal experience in clinical studies would support 55% of pediatricians in their therapeutic choices (especially by way of randomized clinical trials; much less by way of prospective or retrospective surveys), while the support given by the industry representatives’ for information on therapies is felt to be marginal.

More than a half of pediatricians interviewed (56%) are of the opinion that the medical community has made insufficient collaborative efforts in the development of pediatric drugs.

Thirty three percent of companies’ respondents were aware of PIPs submitted by their company. In almost all cases the PIP application was carried out by the headquarters. 

 Also among respondents from the industry, the majority rated the efforts made for the development of pediatric drugs as insufficient.

The results of this survey confirmed some uncertainties still dominating pediatric research among pediatricians, the pharmaceutical/biotech industry, and CROs, as were already highlighted in the previous survey conducted by EUCROF-PWG in 2009. No striking differences can be identified between the outcomes of the two surveys. Most critical difficulties reported in the previous and the current surveys are related to the protocol development, practical issues in the trial management and the need to improve parents’ and patients’ motivation, and retention in studies. A need for support in this respect was indicated especially by pediatricians, who have to face the complex organization of a trial in addition to the daily clinical practice often without dedicated staff. On the other hand, sponsoring companies and CROs need training on the specific regulatory, ethical, and methodological implications of the pediatric clinical development.

It is obvious from these results that the different roles covered by companies sponsoring studies and investigators require mutual support, given the recognized insufficient collaboration among pediatricians and between clinicians and companies. Efforts should therefore be made towards strengthening synergies between the main stakeholders. This interplay should also include ECs, as they represent a major actor in guaranteeing the safety, rights and well being of children involved in clinical research. Such considerations mirror the results of another previous survey conducted among ECs.

Specific operational, ethical, and methodological aspects of pediatric research seem to represent the primary concern, in addition to the increase of the financial burden for the pharmaceutical/biotech industry imposed by the specific pediatric drug developments. Nevertheless, the stimulus given by the Pediatric Regulation to pediatric clinical research is felt as determinant for the availability of drugs specifically designed for children. The perspective of expanding the clinical research in this setting is also welcomed by the pediatric community as a way to increase their experience on specific drugs and on the pediatric clinical trial methodology. The number of pediatric studies newly registered in EudraCT has grown and has reached a level of about 350 per year.7 However it is still uncertain whether this will eventually result in the desired improvement in the treatment of pediatric population, provided that an improvement all across the organizational, ethical, and methodological aspects of pediatric clinical research is needed. This is confirmed by the substantially unchanged perception of difficulties and needs detected in the two EUCROF-PWG surveys.

The results of this questionnaire and also the relatively limited number of responses received may reflect the marginality of pediatric research in Europe. Although such underreporting to the questionnaire represents a limitation of this work, the outcomes of the present survey may represent a basis for further improvement in pediatric research in Europe.  One can conclude from the survey that further support should be given to educational initiatives focused on practical issues in the clinical trial management, ethical aspects, and new methodological approaches, to overcome the challenges of drug evaluation in children and to protect them from unnecessary exposure to experimental drugs.

) is the European CRO Federation with 384 CRO members (approx. 15,000 employees) in Belgium, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Spain, Sweden, The Netherlands, Turkey, and the United Kingdom. EUCROF was founded in October 2005 with the aim of promoting high quality research in Europe by maintaining close relationships with regulatory bodies, the pharmaceutical and biotech industry, and medical research communities. The Pediatric Working Group (PWG) of EUCROF was founded in 2007 and currently consists of ten members focusing on clinical research methodology and ethics in pediatric clinical trials, with the aim of improving clinical research in children and the awareness of the need for clinical studies in children.

The EUCROF Pediatric Working Group is especially thankful to the precious contribution of Carlo A. Rizzi, MD (Medineos, Italy), who enthusiastically collaborated for the realization of the survey (deceased October 15, 2012). Alexandar Cvetkovich Muntañola (INC Research, Spain), Silvia Gasparroni (MediData srl, Italy), Milos Kalina (TFS, Czech Republic), Deirdre McIntosh (McIntosh Scientific, UK), Alejandra Mørk (KLIFO A/S, Denmark), Juergen Schäfer (Conreso GmbH, Germany), and Nicolas Thevenet (France) contributed to the data collection and manuscript.

Thanks to the EUCROF Board for their contribution and continuous support.

Regulation (EC) No 1901/2006 of the European Parliament and of the Council on Medicinal Products for Pediatric Use, Amended by Regulation (EC) No. 1902/2006, 12 December 2006  

M. Dehlinger-Kremer, C.Kreutz, A.Cournot, A.Alemany Pozuelo, K.P.Saalbach, J.Schäfer, P.Smit-Marshall, “Testing Medicines for Children,” 

. Communication from the Commission - Guidance on the information concerning Pediatric clinical trials to be entered into the EU Database on Clinical Trials (EudraCT) and on the information to be made public by the European Medicines Agency (EMEA), in accordance with Article 41 of Regulation (EC) No 1901/2006. Communication No. 2009/C 28/01.

. Report to the European Commission on companies and products that have benefited from any of the rewards and incentives in the Pediatric Regulation and on the companies that have failed to comply with any of the obligations in this Regulation, covering the year 2011. EMA/480331/2012 (12 July 2012).  

A.Svobodnik, A.Alemany, A.Cournot, J.Schafer, M.Dehlinger-Kremer, M.Mas, M.Levy, P.Smit-Marshall,“How to Improve Children’s Research,”

Altavilla A, Manfredi C, Baiardi P, Dehlinger-Kremer M, Galletti P, Alemany Pozuelo A, Chaplin J, Ceci A, “

Impact of the new European  Pediatric regulatory framework on ethics committees: overview and perspectives

. 5-year Report to the European Commission. General Report on the experience acquired as a result of the application of the Pediatric Regulation. EMA/428172/2012 (8 July 2012).

Piergiorgio Galletti, EUCROF PWG and, Pierrel-Research Italy spa, Italy 

Martine Dehlinger Kremer, PhD, EUCROF PGW and ReSearch Pharmaceutical Services (RPS), Germany

Michela Masoero, EUCROF PWG and MediData srl, Italy

Amparo Alemany Pozuelo, EUCROF PWG and TFS, Spain

The Pediatric Working Group of the European CRO Federation conducted a follow-up survey on the status of pediatric clinical trials in Europe.

How to Improve Clinical Research in Children: A Survey on the Perception of European Pediatricians and Industry/CROs

Editor's Note: This version that appeared in the February/March print issue was abridged due to space issues. The full, unabridged version of this article, can be found 

Since January 2007, the European "Pediatric Regulation"

  has fostered ethical research and ensured appropriate authorization and information on medicines for children. The challenging nature of pediatric clinical research requires competence for a full appreciation of the evolving clinical trial methodology in this setting, and a deep knowledge of the specific regulatory requirements. The Pediatric Working Group of the European CRO Federation (EUCROF-PWG) first analyzed the status of pediatric clinical research in Europe by conducting a survey in 2007.

  The results revealed a relatively low number of ongoing pediatric trials while it was expected that the European Pediatric Regulation would stimulate more pediatric research. Based on the information in the public European clinical trials database (EudraCT), the number of authorized pediatric trials, which were part of an agreed Pediatric Investigation Plan (PIP) was 70 in 2011, representing 19% of all pediatric studies.

  According to the recent report of the Pediatric Medicines Section that evaluated research activities during 2011, and that was submitted to the European Medicines Agency (EMA), pharmaceutical companies seem to be meeting their clinical trial obligations in view of a marketing authorization. However, some major deviations from the rules set by the Regulation were observed, in particular, often poorly justified late submissions of PIPs/waiver applications and slow progress of the clinical trial plan.

  Nonetheless, further research incentives are provided by the EMA through the EU Framework Program by funding studies for off-patent medicinal products, in view of the submission of a Pediatric Use Marketing Authorization (PUMA). This program will hopefully give further impulse to pediatric research, but will also amplify the need of quality improvement in pediatric clinical research. 

Another survey performed by the EUCROF-PWG in 2009 aimed to determine the main difficulties and constraints in pediatric research among European CROs, pharmaceutical companies, and Institutional Review Boards/Ethics Committees (ECs).

  Most respondents reported to have conducted less than five clinical trials in children over the last three years. From the responses, it was evident that there was space for improvement in the application of an appropriate methodology, but also a need for support. In particular, support is needed for a better understanding of how to design pediatric clinical trials, how to select appropriate and validated endpoints, how to write good Patient Information Sheets (Informed Consent and Assent Form), and, for ECs, how to gain more experience in the process of pediatric study protocol assessment. 

Of the 350 questionnaires sent out (60% of these to CROs/pharma companies; 40% to pediatricians), 58 were completed and returned. The response rate was 13% from companies and 20% from pediatricians. Respondents who declared not to be involved in clinical research in pediatrics did not provide information so that they were not considered for statistical analysis (N=2). 

Out of 56 respondents evaluated, 29 (51.8%) were pediatricians (mostly from academic institutions or general hospitals), 15 (26.8%) were CROs (mostly country affiliates), and 12 (21.4%) were pharmaceutical or biotech enterprises (mostly ranking within the top 10 in the local markets). The data analyses have been conducted separately for pediatricians (N=29) and sponsors/CROs together (identified hereafter as "companies:" N=27). Sponsors and CROs data were pooled because they have similar roles in carrying out clinical trials. Results are reported as percentages of responses in each category analyzed. 

Knowledge of the Pediatric Regulation 1901/2006/EC. 

The knowledge of the Pediatric Regulation 1901/2006/EC is widespread among respondents (93% within companies; 83% among pediatricians), thanks to a direct involvement in pediatric studies which represent a main source for familiarization with the regulation. Although about 70% of companies and pediatricians believe that the Pediatric Regulation might eventually lead to favorable effects on the therapeutic needs of the pediatric population, it is surprising that there is moderate expectation of the Pediatric Regulation to impact effectively on the availability of new medicines authorized for children, and even less regarding the availability of new indications, new formulations, or an impact on off-patent drugs (Table 1).  

It is noteworthy that the awareness of the likely increase of costs in public health, which can be an effect of the increased research activities and related costs, is evidently low (10% to 11%). 

Experience in clinical research with children. 

63% of companies reported to have started no more than two pediatric studies in the past three years (including 25% of companies reporting no studies at all). Data reported by pediatricians were biased by a high rate on non-responders to this question (56%); the remaining 44% of pediatricians was evenly distributed among the categories listed in Table 2.  

Because clinical research plays a dominant role in the final availability of new drugs, we have investigated the level of experience in the various phases of the clinical development. Good or fairly good experience (relating to a four-level scale: good—fairly good—poor—none) has been reported especially in Phase II and Phase III studies while Phase I has been identified as the area with less experience. Observational studies were mostly performed by pediatricians, as non-commercial sponsors of such studies. Large experience was reported by both companies and pediatricians mainly in oncology, vaccines and hematology. 

Difficulties in performing clinical research with children. 

Difficulties related to protocol development, ethical aspects and practical issues can be encountered in this population. These were investigated (Figure 1) and both practical and methodological aspects appear to be critical while designing and carrying out a pediatric study. Obtaining the parents' understanding and consent is reported as critical and represents a frequent difficulty for the inclusion of a sufficient number of subjects in the studies, the latter being regarded as the most challenging aspect in performing clinical trials in children (74% and 59% for companies and pediatricians, respectively). An additional complication is the collection of biological samples, especially when these are frequent or invasive. 

Methodological aspects are more frequently a matter of concern for the sponsoring companies/CROs, probably because they have regulatory relevance and involve the specific responsibility of the sponsor. Such critical methodological aspects include: getting appropriate patient-derived data, setting validated endpoints that are appropriate for pediatric aims and sample size calculation. Conversely, monitoring and obtaining resources dedicated to the trials, or writing a correct informed consent sheet, are felt to be major hurdles for pediatricians (Figure 1).  

When exploring the need of support, as a consequence of the difficulties highlighted, pediatricians seem to be more demanding all across the wide array of items proposed, especially for the practical and administrative aspects encountered in the conduct of a clinical trial, such as "obtaining appropriate insurance," "receiving IRB approval," or having support for the trial monitoring. These outcomes reflect the difference between investigators and sponsors in terms of structure and organization, whereby the availability of dedicated and experienced staff in the companies allows clearance of such problems in a relatively easy way. The recruitment problem is the only matter of concern that is evenly distributed between companies and pediatricians (as expressed by 44% and 52% of companies and pediatricians, respectively). 

Ethical aspects are critical especially in child-related research, therefore the interaction with ECs should be easy and supported by mutual trust. In general, the competence of ECs is highly appreciated.  

In most cases, the protocol submitted for ethical review is eventually approved by the consulted ECs, however with substantial comments from the ECs in 63% and 45% of instances, as respectively reported by companies and pediatricians, out of the following choices: approval always/in most instances—substantial/frequent comments—frequent rejection. This outcome indicates that the preparation of the study documentation is sometimes insufficient or unclear for a smooth ethics review. 

Availability of information and educational activities. 

In order to improve the awareness of the various aspects of pediatric research, and also to increase skills and competence in the practical aspects of trial conduct, the participation in specific training was felt as useful by most respondents. In fact, the educational support currently available through publications, seminars, trainings, guidelines has been considered inadequate ("less than needed" or "inadequate" amount of information, out of a three-level scale: adequate—less than needed—inadequate) by 74% of companies and 69% of pediatricians. Topics most welcomed by companies were those related to compliance issues, enrollment/retention of patients, informed consent preparation and general ethical issues, pharmacokinetics, European Pediatric Regulation, and PIP preparation. Pediatricians have raised the need for advancement in informed consent preparation and general ethical issues, regulatory affairs and European Pediatric Regulation (Figure 2). 

Main constraints with clinical trials in children. 

According to companies' respondents, clinical trials in children find constraints mainly because of recruitment issues (44%), legislative or administrative issues (30%), and difficulty in obtaining parental consent (30%). Different opinions were expressed by pediatricians, who were most worried by difficulties in obtaining ethics approval (38%), low interest of sponsors (38%), and low financial investments (31%) (Figure 3).  

The future of pediatric clinical research. 

Like the issues described by companies as the main reasons for the slow development of pediatric research, similar concerns are also expected for the future, as being related to recruitment (63%), parental consent (41%), legislation or administrative hurdles (26%), low interest of sponsors (26%), and slow implementation of legislation (22%). Parental consent and recruitment are less frequently mentioned by pediatricians (14% and 10%, respectively), while legislation or administrative hurdles, low interest of sponsors, and slow improvement of legislation are felt by pediatricians as more critical (66%, 55%, and 31%, respectively). 

The majority of the pediatricians (72%) believe that their therapeutic choices would be better supported by personal updates, based on easy access to the available literature, acquisition of experts' opinion, or participation in congresses. Personal experience in clinical studies would support 55% of pediatricians in their therapeutic choices (especially by way of randomized clinical trials; much less by way of prospective or retrospective surveys), while the support given by the industry representatives' for information on therapies is felt to be marginal. 

More than a half of pediatricians interviewed (56%) are of the opinion that the medical community has made insufficient collaborative efforts in the development of pediatric drugs. 

Thirty-three percent of companies' respondents were aware of PIPs submitted by their company. In almost all cases the PIP application was carried out by the headquarters.  

Also among respondents from industry, the majority rated efforts made for development of pediatric drugs as insufficient. 

The results of this survey confirmed some uncertainties still dominating pediatric research among pediatricians, the pharmaceutical/biotech industry, and CROs, as were already highlighted in the previous survey conducted by EUCROF-PWG in 2009. No striking differences can be identified between the outcomes of the two surveys. Most critical difficulties reported in the previous and the current surveys are related to the protocol development, practical issues in the trial management and the need to improve parents' and patients' motivation and retention in studies. A need for support in this respect was indicated especially by pediatricians, who have to face the complex organization of a trial in addition to the daily clinical practice, often without dedicated staff. On the other hand, sponsoring companies and CROs need training on the specific regulatory, ethical, and methodological implications of the pediatric clinical development. 

Specific operational, ethical and methodological aspects of pediatric research seem to represent the primary concern, in addition to the increase of the financial burden for the pharmaceutical/biotech industry imposed by the specific pediatric drug developments. Nevertheless, the stimulus given by the Pediatric Regulation to pediatric clinical research is felt as determinant for the availability of drugs specifically designed for children. The perspective of expanding the clinical research in this setting is also welcomed by the pediatric community as a way to increase their experience on specific drugs and on the pediatric clinical trial methodology. The number of pediatric studies newly registered in EudraCT has grown and has reached a level of about 350 per year.

  However it is still uncertain whether this will eventually result in the desired improvement in the treatment of pediatric population, provided that an improvement all across the organizational, ethical and methodological aspects of pediatric clinical research is needed. This is confirmed by the substantially unchanged perception of difficulties and needs detected in the two EUCROF-PWG surveys.  

The results of this questionnaire and also the relatively limited number of responses received may reflect the marginality of pediatric research in Europe. Although such underreporting to the questionnaire represents a limitation of this work, the outcomes of the present survey may represent a basis for further improvement in pediatric research in Europe. One can conclude from the survey that further support should be given to educational initiatives focused on practical issues in the clinical trial management, ethical aspects and new methodological approaches, to overcome the challenges of drug evaluation in children and to protect them from unnecessary exposure to experimental drugs. 

 PhD*, EUCROF PGW and ReSearch Pharmaceutical Services (RPS), Germany, e-mail: 

, EUCROF PWG and Pierrel-Research Italy SpA, Italy. 

*To whom all correspondence should be addressed.

1. Regulation (EC) No 1901/2006 of the European Parliament and of the Council on Medicinal Products for Pediatric Use, Amended by Regulation (EC) No. 1902/2006, December 12, 2006 

2. M. Dehlinger-Kremer, et al., "Testing Medicines for Children," 

3. European Medicines Agency. "Communication from the Commission—Guidance on the information concerning Pediatric clinical trials to be entered into the EU Database on Clinical Trials (EudraCT) and on the information to be made public by the European Medicines Agency (EMEA), in accordance with Article 41 of Regulation (EC) No 1901/2006." 

4. European Medicines Agency. "Report to the European Commission on companies and products that have benefited from any of the rewards and incentives in the Pediatric Regulation and on the companies that have failed to comply with any of the obligations in this Regulation, covering the year 2011." 

5. A. Svobodnik, et al., "How to Improve Children's Research," 

6. Altavilla A, et al., "Impact of the new European  Pediatric regulatory framework on ethics committees: overview and perspectives," 

7. European Medicines Agency. "5-year Report to the European Commission. General Report on the experience acquired as a result of the application of the Pediatric Regulation." EMA/428172/2012 (8 July 2012). 

8. A. Svobodnik, et al. "How to Improve Children's Research," 

A survey on the perception of European pediatricians and industry/CROs