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Growing Need for More Clinical Trials in Pediatrics

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By: Erin Turbitt, PhD

Source: Flickr by Claudia Seidensticker via Creative Commons

      There have been substantial advances in biomedical research in recent decades in the US, yet children have not benefited through improvements in health and well-being to the same degree as adults. An illustrative example is that many drugs used to treat children have not been approved for use by the Food and Drug Administration (FDA). Comparatively, many more drugs have been approved for use in adult populations. As a result, some drugs are prescribed to pediatric patients outside the specifications for which they have been approved for use, referred to as ‘off-label’ prescribing. For example, some drugs approved for Alzheimer’s Disease are used to treat Autism in children. The drug donepezil used to treat dementia in Alzheimer’s patients is used to improve sleep quality in children with Autism. Another example is the use of the pain medication paracetamol in premature infants in the absence of the knowledge on the effects among this population. While decisions about off-label prescribing are usually informed by scientific evidence and professional judgement, there may be associated harms. There is growing recognition that children are not ‘little adults’ and their developing brains and bodies may react differently to those of fully developed adults. While doses for children are often calculated by scaling from adult dosing after adjusting for body weight, the stage of development of the child also affects responses to drugs. Babies have difficulties breaking down drugs due to the immaturity of the kidneys and liver, whereas toddlers are able to more effectively breakdown drugs.

The FDA requires data about drug safety and efficacy in children before issuing approvals for the use of drugs in pediatric populations. The best way to produce this evidence is through clinical drug trials. Historically, the use of children in research has been ethically fraught, with some of the early examples from vaccine trials, such as the development of the smallpox vaccine in the 1790s. Edward Jenner, who developed the smallpox vaccine, has famously been reported to have tested the vaccine on several young children including his own without consent from the children’s families. Over the next few centuries, many researchers would test new treatments including drugs and surgical procedures on institutionalized children. It was not until the early 20th century that these practices were criticized and debate began over the ethical use of children in research. Today, in general, the ethical guidance for inclusion of children in research specifies that individuals unable to exercise informed consent (including minors) are permitted to participate in research providing informed consent is gained from their parent or legal guardian. In addition to a guardian’s informed consent, assent (‘affirmative agreement’) of the child is also required where appropriate. Furthermore, research protocols involving children must be subject to rigorous evaluation by Institutional Review Boards to allow researchers to conduct their research.

Contributing to the lack of evidence of the effects of drugs in children is that fewer clinical trials are conducted in children than adults. One study reports that from 2005-2010, there were 10x fewer trials registered in the US for children compared to trials registered for adults. Recognizing the need to increase the number of pediatric clinical trials, the FDA introduced incentives to encourage the study of interventions in pediatric populations: the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). The BPCA delays approval of competing generic drugs by six months and encourages NIH to prioritize pediatric clinical trials for drugs that require further evidence in children. The PREA requires more companies to have pediatric-focused drugs assessed in children. Combined, these initiatives have resulted in benefits such as improving the labeling of over 600 drugs to include pediatric safety information, such as approved use and dosing information. Noteworthy examples include two asthma medications, four influenza vaccines, six medications for seizure disorders and two products for treating migraines. However, downsides to these incentives have also been reported. Pediatricians have voiced concern over the increasing cost of some these drugs developed specifically for children, which have involved minimal innovation. For example, approval of liquid formulations of a drug used to treat heart problems in children has resulted in this formulation costing 700 times more than the tablet equivalent.

A further aspect that must be considered when conducting pediatric clinical trials is the large dropout rates of participants, and difficulty recruiting adequate numbers of children (especially for trials including rare disease populations) sometimes leading to discontinuation of trials. A recent report indicates that 19% of trials were discontinued early from 2008-2010 with an estimated 8,369 children enrolled in these trials that were never completed. While some trials are discontinued for safety reasons or efficacy findings that suggest changes in standard of care, many (37%) are discontinued due to poor patient accrual. There is insufficient research on the factors influencing parental decision-making for entering their child to a clinical trial and research into this area may lead to improvements in patient recruitment for these trials. This research must include or be informed by members of the community, such as parents of children deciding whether to enroll their child in a clinical trial, and disease advocacy groups. The FDA has an initiative to support the inclusion of community members in the drug development process. Through the Patient-Focused Drug Development initiative, patient perspectives are sought of the benefit-risk assessment process. For example, patients are asked to comment on what worries them the most about their condition, what they would consider to be meaningful improvement, and how they would weigh potential benefits of treatments with common side-effects. This initiative involves public meetings held from 2013-2017 focused on over 20 disease areas. While the majority of the diseases selected more commonly affect adults than children, some child-specific disease areas are included. For example, on May 4, 2017 public meeting was held on Patient-Focused Drug Development for Autism. The meeting included discussions from a panel of caregivers about the significant health effects and daily impacts of autism and current approaches to treatment.

While it is encouraging that the number of pediatric trials are increasing, ultimately leading to improved treatments and outcomes for children, there remain many challenges ahead for pediatric drug research. Future research in this area must explore parental decision-making and experiences, which can inform of the motivations and risk tolerances of parents considering entering their child to a clinical trial and potentially improve trial recruitment rates. This research can also contribute to ensuring that clinical trials are ethically conducted; adequately balancing the need for more research with the potential for harms to pediatric research participants.

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Written by sciencepolicyforall

May 24, 2017 at 5:04 pm