The EU has recognised that paediatric clinical trials are essential but recruiting patients remains a huge challenge
Ask any mum or dad if they would be happy enrolling their child in a clinical trial and all but the most informed would recoil in horror: "Let my child be a guinea pig? No thank you."
Adult clinical trials already present considerable challenges associated with recruitment and retention. Factor in that a child's legal representative must consent and the child assent to be enrolled, and the prospect of completing a paediatric clinical trial at all, let alone on time, is even more daunting.
Recruiting patients to clinical trials remains the biggest hurdle to completing studies on time. Around 60–70 per cent of clinical trials do not meet their enrolment targets and this has a serious impact on collection of timely data and ultimate product sales.
Lack of accessible information is at the core of the enrolment problem; recent research showed that out of more than 1,500 potential adult subjects, 41 per cent said that there was not enough information about clinical trials or that it was hard to access.
Concerned by the lack of medicines specifically for use in children, the European Commission gave considerable legal powers to the European Medicines Agency (EMEA) to mandate and reward companies for providing valuable paediatric data.The resulting regulation on medicines for paediatric use became law in all member states on January 26, 2007.
As of January this year, pharma companies that submit an application for marketing authorisation (MA) have to provide either the results of studies in children, conducted in accordance with an approved Paediatric Investigation Plan (PIP), or an EMEA decision on a deferral (where the PIP may delay the authorisation of the medicinal product for use in adults), or a waiver. This applies for a new medicinal product, an extension of indication, a new route of administration, or a new pharmaceutical form of a medicinal product already authorised in the European Economic Area.
Waivers may be granted for medicines intended to treat conditions that only occur in adults (class waiver), as agreed by the Paediatric Committee (PDCO), and for medicines that may be unsafe or ineffective, or do not offer significant therapeutic benefit and/or fulfil a therapeutic need in children (product-specific waiver).
In return, once MA is obtained in all member states and study results are included in the product information, the medicine is eligible for six-month patent extension.
For orphan drugs fulfilling the same requirements, an additional two years of market exclusivity will be granted beyond the 10 years to which orphan medicinal products are entitled.
Not small adults
Children are not simply small adults and respond very differently to medications and information. Paediatric clinical trials must be tailored to the patient group as well as the disease and therapeutic area.
The ethical debate around conducting clinical trials in children seems to have been settled with the general consensus that it is unethical not to conduct clinical research in the paediatric population.
Up to 50 per cent of the drugs on the European market have not been specifically tested on children, so there is often no knowledge about potential adverse effects, optimum dosing, preferred administration, or if the medicine works at all in this population.
In the last two decades, research has begun to involve children as participants in their own right, whose views and experiences are valued. Children are better informed than ever and are given their own voice in the media, government and indeed most areas of public life.
The process for testing medicines in children is rightly robust and tightly regulated; all study protocols must be submitted to ethics committees and the Institutional Review Board (IRB) before they start. Writing these study protocols is a specialist skill and it is advisable to enlist the help of an expert.
Everyone in the loop
According to published ethical considerations for clinical trials on medicinal products within the paediatric population, the child is a minor and therefore unable to provide legally binding consent, so specific and written informed consent must be sought from the parents/legal representative on the child's behalf, prior to enrolling a child in a trial.
When providing information to parents/legal representatives, it is imperative to consider the fear and uncertainty they have, especially if they are inexperienced with respect to the child's condition. The parents/legal representative might need more detailed information, and more time, also to reflect on the implications of consenting on someone else's behalf.
In addition to legally binding consent, ethical guidelines state that a child's assent should be sought using age-appropriate information.
Children should be fully informed in a way that is familiar to them and they are comfortable with. It is vital that children are told about all possible risks and benefits associated with clinical trials so they are able to make an informed decision about their involvement.
The standard-issue, long and technical informed consent document is not appropriate for children to assent. Information needs to be relevant to particular age groups, using basic language and preferably with illustrations. Dialogue with the research team also plays a big part and can be facilitated with picture books and puppets for young children or computer-generated content, and text messaging for those who are older.
Consent and assent, are dynamic, continuous processes that need to be considered throughout the trial. Information should be collected at key stages, such as at repeat visits and through discussions between all parties. Every effort should be made to ensure that children and their parents/legal representative feel comfortable to continue with the trial, especially as new information comes to light.
Age-appropriate information will also help with participant retention and compliance, but methods for children to provide honest feedback and communicate any concerns they may have are as important.
Don't forget other concerned parties, such as siblings and close friends. Frequent visits to the hospital and more attention being given to a brother or sister can cause anger and frustration. Information tailored to siblings, explaining why the visits are necessary or simply improving their understanding of their sibling's condition, can go a long way to alleviating any lack of understanding.
Materials and support tools must not induce or incentivise the child to continue the trial but aim purely to inform and educate. Everything must pass rigorous testing from ethical committees. It is advisable to test any supporting trial information with your audience; focus groups with parents/legal representatives of children with a specific condition, as well as the children themselves, to ensure you have the right content format and tone.
Do not underestimate the importance of the research nurse in facilitating children's participation through communicating information and creating partnerships with them; as such, consider including a training component for those who will be using the materials, to ensure that they are used correctly.
There is a requirement now to increase the development and testing of medicines specifically for use in children. Based on US experience, the EU paediatric regulation will ensure that this is the case. Between 1997 and 2005, additional labelling information on safety, efficacy, dosing and unique risks in children has been included on 100 drugs in the US. Manufacturers have conducted more than 250 paediatric studies for 125 products. In contrast, in the seven-year period before 1997, only 11 such studies were carried out.
Retention is key
In the absence of a deferral, delays in the paediatric clinical trial programme may well jeopardise timely marketing authorisation of the product. For this reason, it is critical that recruitment and retention of paediatric trial subjects is optimised; quality patients in means quality data out, and on time. Good communication plays an important role in achieving this.
Communication should be factored from the outset and not be given a cursory last-minute thought or used as a rescue remedy as a trial falls behind recruitment targets.
All possible information must be provided to all those involved at each stage of the clinical trial process. This will ensure that parents/legal representatives understand fully what they are consenting to, that the child's fears are allayed and they understand fully what is going to happen at the next visit and that the research team is able to communicate clearly what is involved in the trial to different age groups from the outset. Only this way will you have mums and dads saying: "Yes, we understand what's involved so does our child. We'd like to be enrolled."