Clinical Risk >
Volume 14, Number 6 >
Pp. 215-217
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Patient safety |
Email: Jimappleyard2510{at}aol.com
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The lack of appropriate dosage forms for many ‘essential medicines’ for the main five treatable conditions causing the deaths of 10 million children worldwide under the age of 5 years are a major reason why countries are not achieving their millennium developmental goals.
There has been understandable reluctance to undertake the necessary research on children. The reasons for this are reviewed. The existing levels of protection for child subjects worldwide are insufficient. Key principles are suggested both to encourage clinical research and to ensure adequate protection for children around the world.
Physicians are taking significant risks when they treat children with medications that may have not been adequately tested for their efficacy and safety during childhood. Such treatment decisions have to be taken in everyday clinical practice. They tend to be based on ‘trial and error’ from the physicians' personal experience, advice from colleagues, anecdotal reports from the literature and extrapolations from adult studies.
In addition medication errors are a constant hazard in paediatric clinical practice. Continuous changes of the dosage regime that are necessary during a child's growth and development make the calculation of the correct dose for each child difficult. The frequent use of off-label medicines with extemporaneous formulations or physician or nurse-made manipulations provide optimal conditions for these medication errors.1 Ingredients or excipients for improving solubility, sterility and the taste of children's medicines may also cause toxicity (e.g. benzyl alcohol and diethylene glycol).
Severe adverse drug reactions in children are not always fully reported. Some of the most dramatic examples of these are the apnoea caused by too large a dose of phenobarbitone, pethidine and prostaglandin, convulsions following the administration of theophylline and hepatic failure associated with high doses of paracetamol (acetaminophen).
Recognizing these significant risks in the care of their patients, practicing pediatricians, particularly in the USA pressed for changes in the regulation of medicines for children. In 1996, the American Academy of Pediatrics (AAP)2 reported that only a small fraction of all drugs and biological products marketed in the US at that time had had clinical trials performed in paediatric patients. A majority of marketed drugs are not labeled for use in paediatric patients. The AAP also pointed out that many drugs used in the treatment of both common childhood illnesses and more serious conditions carried little information in the labels about use in paediatric patients.
In order to address these inadequacies, the Food and Drug Administration (FDA) published regulations (see http://www.fda.gov/) which ensure that manufacturers specifically examine the drugs' effects on children if the medications were to have clinically significant use in children.
Paediatric research has since been encouraged by the paediatric exclusivity provision of the ensuing Food and Drug Administration Modernisation Act of 1997. This extended patent protection to give pharmaceutical companies an additional six months of marketing exclusivity if they do studies in children requested by the FDA. The FDA's ‘pediatric rule’ required paediatric studies under certain circumstances.3
In January 1997 the National Institute of Health (NIH), a major funder of clinical research worldwide, developed the policy that children (defined as individuals under the age of 21 years) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
In the European Union, the Council resolved in 2000 to set their objectives for regulation on medicinal products for pediatric use, which aimed to stimulate research into and to increase the availability of medicines for children.4 Draft regulations were consulted upon in 2004 which proposed the establishment of a European Paediatric Board with the European Medicines Evaluation Agency, that all new medicines should have a paediatric investigation plan with a six-month extension in patent term, and a new system of granting paediatric use marketing authorizations (PUMAs) for existing products.5 These regulations came into effect in 2006 and already they have had a positive effect on promoting research in Europe (see http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/medchild_en.htm).
In 2007 the World Health Assembly adopted a resolution calling for a more rational use of and better medicines for children. The World Health Organization (WHO) noted that around 10 million children under the age of 5 years die every year. Many of these deaths are from treatable conditions, the most common of which is pneumonia. Others include diarrhoeas, malaria and HIV/AIDS. Few countries are on track to achieve the WHO Millennium Developmental Goals (MDGs), especially goal 4 which aims to reduce the mortality of children under 5 years old by two-thirds between 1990 and 2015.
Even though effective interventions exist, these may entail the use of ‘essential medicines’ which do not exist in dosage forms for children, particularly in low- and middle-income countries. Lack of the availability of these essential interventions has been identified as a major reason for countries not making adequate progress towards their MDGs. The WHO publication ‘Child Health Research – a foundation for improving child health’6 asserts that ‘Child health research must address the leading causes and determinants of morbidity and mortality at different stages of a child's development and identify and implement interventions that address these causes’.
Six main areas for research are identified:
Though the FDA, the European Commission and WHO have brought a new emphasis on research on drug development for children, there remains a reluctance to include children in this research and especially in clinical trials. There are several reasons for this: firstly, children's increased vulnerability and therefore risks are increased both in the short and long term. There is an understandable parental reluctance to add any risk to their children's welfare.
Secondly, because of children's age-specific needs, they have different physiological, psychological and pathogenic features occurring at the different ages and stages of their growth and development as well as sex and ethnicity, from the premature newborn infant through adolescence. Such factors increase the complexity and cost of research.
Thirdly, the high cost and low financial return have made pharmaceutical companies reluctant to invest.
And fourthly, outside North America, Europe and Japan there is a lack of universal ethical and regulatory guidance for researchers and sponsors upon which parental trust depends.
There are currently several layers of ‘protections’ for child subjects in clinical research:
The Belmont Report13 highlighted three of these – respect for persons (autonomy), beneficence and justice. But recent publicity about adverse events in clinical trials has revealed serious failures to address one or all four of the other listed principles.
Child subjects are indeed vulnerable and do need special protections beyond that provided by the World Medical Association's (WMA) Declaration of Helsinki9,14 particularly with regard to consent/assent, the assessment of risk and in research study designs.
To address this deficit, amendments to the section on research in the WMA's Declaration of Ottawa on the Right of a Child to Health Care have been suggested.15
Each statement is self-standing but all are inter-related. They are that:
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Minimal risk involves procedures, questionnaires, observation and measurements carried out in a child-sensitive way.
Greater than minimal risk involves invasive procedures or therapies. These should be carried out only when:
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The preclinical safety and efficacy data are preconditions for the start of a paediatric clinical trial.
The study must be guaranteed to be conducted by experts competent in childhood diseases and disorders, who are empathetic and truly conversant with children, parents and the legal requirements where the interests of the child are paramount.
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Further work needs to be done on these statements when they are sent out for consultation among the 80 national medical associations which are members of the WMA. They need to build on the fundamental ethical principles in the WMA's Declaration of Helsinki, which is being crafted to protect all ‘subjects’ who participate in clinical research worldwide. These statements should act as a reference to physicians throughout the world, from which each national medical association can derive its own culturally-sensitive guidelines. With the trust that is earned when medical researchers act in an ethical and transparent manner to prevent the ethical abuses of the past15 and to plan for the future,16 it is hoped that more parents will recognize the benefits that research on their children can bring to them and all children worldwide.
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