Conducting clinical studies in children is often a difficult undertaking. However, with proper planning and using the right resources, one can run safe, timely and successful trials in this challenging population.
It’s no secret that clinical research has steadily become more challenging and costly. Patients are difficult to recruit, regulations are more stringent and complex, and patient expectations are very high. However, these realities of our field can be seen no more clearly than when attempting to develop medicines for children. With the advent of legislations aimed at boosting paediatric drug trials, such as the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) in the US and, most recently, the 2007 Paediatric Regulation in the EU, paediatric clinical research is a hot topic for regulatory agencies and subsequently for sponsors as well.
Goals of paediatric development
Considering that the needs of the patient are always our first priority, our primary goal as researchers is to decrease the disease burden on the subject (and ultimately the paediatric population as a whole) while minimising their risk and discomfort. In order to reach this goal and to maximise time and resources, one must try to optimise protocol design, and boost subject recruitment and retention while adhering to applicable regulatory guidelines. Once these patient-centred goals are met, the sponsor should then seek to achieve alignment of the clinical needs and regulatory requirements with the commercial objectives of the company.
Until recently, most drugs used in children did not have paediatric labelling or the clinical research to support that labelling. Barriers to paediatric research that led to this lack of information include logistical and technical constraints, limited study populations, and most importantly, the economic disincentive to run expensive trials often for a very small return on investment. Additionally, efforts over the last half of the 20th century, such as the Declaration of Helsinki, intended to protect human subjects (particularly “vulnerable” populations such as children), while going far to achieve that goal, had the unfortunate side effect of severely limiting much of the research on those populations as the ethical bar was raised. In 1963, Dr Harry Shirkey first used the term, “therapeutic orphan” to describe the predicament that children are in within the context of inadequate drug research.
The current environment
Patient safety and the use of evidence-based medicine are of vital importance to the current medical treatment paradigm. In order to make good clinical decisions, healthcare providers need information that is only available from well-executed clinical research across all age groups. This information now becomes even more critical as many more children are taking prescription medication than ever before. A recent study of US prescription claims data from 2002 to 2005 of children 5 to 19 years of age revealed that the use of chronic medication (such as used in type 2 antidiabetic, ADHD and asthma) increased, often dramatically, across all therapy classes assessed. However, compare these findings with those obtained in a 2008 University of Michigan study which showed that 77 per cent of parents want only FDA-approved medicines for their children, yet only 30 per cent said they would allow their children to participate in research. In addition to reasonable concerns over the safety of their children, the public generally have a negative view of the pharmaceutical industry and are often wary of the healthcare system in general.
So, as researchers, we must balance the need for creating more paediatric drug knowledge with limiting exposure to risk in this unique population. We must also contend with the reality that parents demand only the best for their children, but are often unwilling to put them in clinical studies that yield the critical information needed to provide this quality data. With this in mind, how does one approach the enigma of paediatric research?
Paediatric study design
A well-written and straightforward protocol is the cornerstone of a good trial, and will go a long way towards assuring reliable data and optimal enrollment timing. Choosing clear and reasonable endpoints that answer the most important clinical questions being asked in the study should always be a priority, and in order to maximise the pool of potential subjects, one should minimise inclusion / exclusion criteria to only what’s absolutely necessary.
One fundamental step towards optimal recruitment and retention would be to ensure that minimum burdens are placed on subjects and their patients. Anyone with children knows how busy life can be! Consider the modern realities of single parent households, families where both parents work outside of the home, and how today’s children are woefully overscheduled. Clinical researchers need to design studies around the lifestyles of all impacted parties, keeping in mind that parents work, older children attend school and that there may be siblings who require time and attention as well. This does not leave much time for participation in a complicated and / or lengthy clinical trial. Some of the ways that help to streamline trials include limited diary and recordkeeping requirements for the subjects, and minimal lab draws and / or study visits. Consider scheduling enrollment period during “child-friendly” times such as over summer vacation, allowing less intensive follow-up visits to be done during the school year. Also, if at all practical, substituting house calls for clinic visits can be a tremendous aid in assisting families to participate.
Fear of procedures is big concern for children. This should be addressed upfront, and all efforts to minimise the number of procedures (particularly invasive ones such as needle sticks) should be taken. When procedures are unavoidable, pain and discomfort need to be decreased as much as possible. Measures to achieve these ends include the use of topical anaesthetics (e.g. EMLA cream) for all needle sticks, and attempting to use facilities that have professionals (i.e. child-life specialists) whose job it is to minimise the negative impacts of medical treatment, including procedures, through age-appropriate education and interaction and a variety of distraction or coping techniques (e.g. bubble-blowing, story-telling).
Recruitment and retention
Parents or guardians are generally very concerned about their children’s health, even if they are not necessarily as vigilant about their own. Because of regularly scheduled well-child visits and the need for frequent vaccinations, families are often in regular contact with their paediatricians. Therefore, parents usually put great trust in the opinion of their paediatrician and generally consult them about what they think about the clinical study.
Protocols, informed consent forms and other documents that will be read by parents and healthcare providers need to be straightforward and well written, and also fully explain the study’s procedures, schedules, and risks and benefits. Parents, particularly those with children who have rare or serious diseases, or have multiple health problems, are very information-literate and will go onto the Internet not only to do research, but to share the details of the trial and compare notes with others in chat rooms, blogs or on specific support group sites. Safety is of paramount importance, and all current preclinical and clinical safety data derived from other paediatric trials, adult trials and, if applicable, marketing experience should be provided. Sponsors should be prepared to answer very pointed questions about their trial in an honest, intelligent and clear way.
Parents expect nothing less than complete transparency and an experience that preserves the dignity of their children. Poorly designed trials or research groups who provide anything less than excellent service and caring will not only fail to recruit or retain subjects, they will quickly gain a bad reputation as word spreads fast among online communities of parents and healthcare providers.
Use the best resources available
There are people and resources with the paediatric expertise that can assist you with your studies. First, consider those who are close at hand. Identify colleagues with paediatric experience and training within your own organisations who can assist with the review of paediatric clinical protocols and trial data, address national and global paediatric policy and regulations, and work with others to create unified paediatric processes, templates etc. Outside your organisation, there are investigators, study coordinators, IRBs and CROs with expertise to study drugs in children who may be available to help you. There are many dedicated paediatric research centres and collaborative research groups (e.g. Children’s Oncology Group) who already have networked centres able to provide access to sub-specialists and their patients. Paediatric formulation experience is also generally needed as many adult drug forms or strengths are inappropriate for children. This may mean formulating syrups, liquids or chewable tablets with palatable flavourings suitable to children. Sponsors should allow adequate lead-time for reformulation efforts. For laboratory testing, analytical methods that allow for smaller clinical sample sizes should be sought out. Finally, one should consider unique solutions such as adaptive clinical study designs, and take a global approach to studies. A successful study involves identifying locations of subject populations and centres of excellence that have the necessary capabilities. This may involve considering the inclusion of subjects in the developing world where opportunities to make a significant impact on the health of children are numerous.
While running clinical studies on children is difficult, it is by no means impossible. Success not only requires that researchers expand their skill sets and acquire the specialised resources to assist them, but it also calls for a personal commitment to this very special population of subjects and the families that care for them.
1. Shirkey, H. Therapeutic orphans. J Pediatrics. Vol. 72, No. 1, Jan 1968. 119-20.
2. Cox, E.R., et. al., Trends in the Prevalence of Chronic Medication Use in Children: 2002–2005. Pediatrics. Vol. 122 No. 5, Nov 2008, e1053-e1061
3. C.S. Mott Children’s Hospital National Poll on Children’s Health Vol. 3, Issue 5, May 12, 2008