CHALLENGES AND SOLUTIONS
There are a number of challenges in order to conduct efficient and controlled trails in children. Before 1966, children were experimented upon with very little protection for their susceptibility. Certain rules and regulations were later formulated to protect them. Most important reason for the lack of research on children is due to the fact that children cannot provide informed consent for themselves and hence they are more vulnerable than competent adults. There was a growing preference to engage adults for trials and this brought the existence of the term 'therapeutic orphan' in 1968 to describe children effectively excluded from research. The Jesse Gelsinger incident reinstated this statement further - In 1999, 19-year-old Jesse died while participating in a gene transfer trail, hence proving one of the gravest outcomes in pediatric research that created a scare amongst people. This not only questioned the efficiency of clinical trials in children but also brought about the decline of gene therapy. Gene therapy since then has never picked up much.
However, with the European and Non-European regulations medicines for pediatric-use coming into effect in 2007, it compels the pharmaceutical companies to undertake trails within pediatric populations. With this law in place over 80 drugs have now been tested on children and labeling has changed accordingly. For instance, Ibuprofen, one of the most common over-the-counter drug on which parents rely on to reduce fever in children, had been used off-label until recently. With the large studies conducted on young children and adults the dose has been considered to be safe and effective for over-the-counter use. It is prudent to conduct pediatric trials after phase I and phase II trails of any drug. If the severity of the disease is large in adults and children then it should begin early on in children too. They should however be tested for efficacy, tolerability and safety in animals thoroughly first.
Another initial downer for the research on children was the lack of incentives for industry in a free market economy to sponsor pediatric clinical trails. Most drugs developed for adults by industries are successful due to the large number of consumers, the prevalence of these conditions are common and hence the financial rewards are numerous. Children health problems are not that severe; for instance, asthma in majority of children can be controlled with minimal and inexpensive treatment. The incentives for pharmaceutical companies are small and there is a potential for damaging publicity and financial liability when adverse events occur in children. This has now changed with the FDA issuing the Pediatric Exclusivity Incentive Program, which provides six months of marketing exclusivity to sponsors that conduct pediatric clinical trails. FDA has now taken a carrot and stick approach to encourage pediatric studies. Carrot is the voluntary pediatric exclusivity provision of the FDA Modernization Act of 1997(FDAMA) which was reinstated in January 2002 and extended through 2007 as the Best Pharmaceutical for Children Act, BPCA. Stick being Pediatric Research Equity Act (PREA) which allows FDA to require pediatric studies. These legislative efforts had a positive impact. In the US since 2004 approximately 150 approved drugs have been tested in the pediatric population. The legislation is now focusing on funding and organization of these clinical trials, however it overlooks the trails conducted by academic institutions. It is seen that the large market for adult drugs is still more than two-fold the incentives provided to industries to conduct pediatric research and has hence under-represented certain age groups. Further incentives must be provided for more than just regulated drugs.
Perspectives of clinicians can also pose as a barrier for the recruitment of pediatric subjects. Clinicians are asked to recruit children for research studies. This involves time and effort as there is consent to be taken from parents and describe the studies to both the children and parents. This time could be used to treat patients instead. Other barriers are forgetfulness/ lack of awareness of trails, time and financial constrains, extra work involved, lack of resources, ethics requirement concerns on doctor-patient relation, fear of losing patients, concerns about patient's health, discomfort with randomization, preference for particular treatment, dislike of loss of autonomy and mistrust in researchers.
To address this concern, patronage is very essential in helping associations and agencies to listen to the voices of children who would otherwise not be heard as they cannot speak for themselves. Training is important and pediatric educators have identified this problem in encouraging the trainees to pursue research careers and challenges to obtain funding for their own research. Initiations have been made recently to help clinicians pursue their careers and educate them about the different clinical trials; this has been done through the Pediatric Scientist Development Program and the Child Health Clinician Scientist Program in the USA and Canada. FDA is closely working with AAP (American Academy of Pediatrics) to educate clinicians about the labeling changes through an online continuing medical education program called 'Pedialink'. These programs help to develop the skills needed for a new generation of clinicians who can design innovative trails and also overcome the barriers in employing children in those trials.
Parents' worry poses another hindrance to their kids' involvement in trials. They seem and always do have a say in the participation of their children in the clinical trials. Allowing children to participate in trials is an uncertainty. The parents are always concerned about the long-term effects in minors (physical and physiological harm). The enrollment of healthy children who have no potential harm to the particular disease/condition for which the research is conducted is always a question in parents' mind. According to parents, if their child is in no danger from the disease or does not have the condition at present why put their child at risk is their argument. Sometimes the logistics and financial costs are overwhelming and hence the parents have to think twice. Taking time off from their paid work, language barriers, cultural differences and fear of exploitation and ethnic stereotype are some other anxieties.
Children too are dependent on the parent/guardian invariably for everything and in the case of trails they have to depend on the elders for their transport and assent. Children at times feel embarrassed about these things in front of peers. There sometimes is a discord between the parents and the children too about their participation in the trials. Children are sometimes scared to be approached by strangers and fear about things like how the medicine would taste, if they are not going to enjoy taking it, if they have to give up their play time to go for these trials.
Continued efforts are being made now to educate parents and children understand the benefits and risks about the clinical trails, which have increased the recruitment rates. Conducting either one-on-one sessions or having open educational sessions about the trails have helped in this aspect. Transparency and clarity around the distinction between consent to treatment as opposed to giving permission for a child to participate in a trial would be helpful. Face to face recruitment methods help parents and children to understand the trails better and put them at ease to take the decision. Many parents have suggested getting opinions from their personal clinician and also get in touch with previous parents who have had experience with the trials to help them decide. Children's concerns and queries must also be dealt with as the child must have a basic understanding of why he or she is taking part in the research. It would be a shame to have children and parents dissent because they are presuming there would be procedures and protocols which are actually not a part of the study. Strategies for successful recruitment of children in trials are development of incentives, motivators and effective clinical trial design.
Ethically speaking the motivators, incentives and trials must not attempt to offset the inappropriate risk. Research on the implications of cultural sensitivity for recruitment also indicates that researchers must invest time and effort to assemble a panel of cultural experts to provide advice about group - specific strategies to build trust and cultural sensitivities with vulnerable populations. Having at least one co investigator who is a member of the study is as an asset. Parents need to accompany children or assist them in the payment of the transportation during study. In order to avoid this, trials should be conducted during regular clinic visits or the costs for the transport must be reimbursed. Institutional Review Board and the granting agencies must try their level best to reduce the financial barriers and other concerns that may discourage the parents consent to their children participating in the trials.
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A Scientific Writer