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

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 Applied Clinical Trials 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.

Methods

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.

Results

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. 

Requirements for the AF

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. 

Signature requirement for the AF:

• 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 and compensations

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.

Conclusion and next steps

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.

Alexandar Cvetkovich Mutanola, with EUCROF and INC Research, Spain; Martine Dehlinger-Kremer, with EUCROF and SynteractHCR, Germany; Erik Hamminga, with EUCROF and Chiltern, Netherlands; Michela Masoero, with EUCROF and MediNeos, Italy; Alejandra Mørk, with EUCROF and KLIFO, Denmark; Daria Podgórska, with EUCROF and Appletree-CIG Group AG, CH; Sofia Romboli, with EUCROF and Zeincro Hellas, Greece; Jürgen Schäfer, with EUCROF &, Conreso GmbH, Germany