As potential participants in research, children have special needs because of their vulnerabilities and developmental idiosyncrasies. Doctors involved in research on children must respect the autonomy and the individuality of children, be aware of children’s apprehension about medical procedures, and acknowledge the fundamental biological differences between adults and children.The following four principles were announced by the United Nations General Assembly in 1989 as the outcome of a Convention on the Rights of the Child:
Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults. For example, in pharmacokinetics, there are differences in metabolic pathways, in organic functions, and in metabolic rates. In pharmacodynamics, differences exist in receptor functions, effector systems, and homeostatic mechanisms. Growth and development influence side effects, and the dose of medications is dependent on body weight or surface area. Finally, age influences severity of disease, pathological agents, and natural history. These differences imply that extrapolation of adult data on medicinal products for the pediatric population is inappropriate.
Furthermore, childhood has several ages and stages. Studies must be performed on specific age groups such as premature newborns, full-term newborns, infants and toddlers, older children, and adolescents.
The FDA, EMA, and other authorities state that research in children should be supported and encouraged. The Committee for Proprietary Medicinal Products (CPMP) recommends the following categorization of products to be studied in pediatric clinical trials: 7
WCCT Global’s Pediatric Center of Excellence, which includes more than 5 leading Principal and Sub Investigators in this important field, works with sponsors in both early development and late stage research to offer strategies that more rapidly demonstrate the Pharmacokinetics, Safety, Tolerance and Pharmacologic Activity of the new compounds being tested in children.
WCCT Global has carried out studies in children in the following therapeutic areas:
Because WCCT Global has access to healthy volunteers and patients of diverse ethnic lineage they work with sponsors to rapidly get the information necessary to launch a Global Development Program months ahead of the classic development paradigms, hence providing a strategic advantage to those served.
One ethical issue pediatric researcherfaces is that clinical research involves some risk to the subject. Research procedures range from techniques involving minimal risk, such as questioning, observation, and measurement carried out sensitively, to techniques involving higher risk, such as chemotherapy and surgery.
At what point in a drug’s development should research in children begin?
The International Conference on Harmonization of Technical requirements for registration of Pharmaceuticals for Human Use (ICH) makes several suggestions regarding the inclusion of children in the development program of medicinal products. For medicinal products for diseases affecting children exclusively or predominantly, the entire development program can be conducted in the pediatric population beginning with phase 1 or 2 trials. For products for serious diseases affecting both adults and children for which a sufficient treatment does not currently exist, the development program should be conducted early in the pediatric population after safety and tolerability data have been obtained in adults (phase 2 or 3). For other products for serious diseases, the product usually should not be tested in the pediatric population until phase 2 or 3, after substantial experience in adults.
In all cases, efficacy, pharmacokinetic, and safety studies must be performed first in animals, as is required for adult studies. Placebo-controlled trials are inappropriate in pediatrics when risk would be increased by withholding a proven, effective treatment.
WCCT Global feels that no child should participate in a study unless a benefit to children in general will result. The ethical imperative to obtain knowledge of the effects of medicinal products in pediatric patients has to be balanced against the ethical imperative to protect the individual child in clinical studies and respect his/her integrity and personal dignity.
The 4 Basic tenets of Good Clinical Practice are fundamental principles to guide research in children:
From these ethical principles, general guidelines for good clinical practice in pediatric research can be derived. Trials should focus on the knowledge, cure, relief, or prevention of diseases of children. Biomedical studies must be devoted to reducing suffering and improving the prognosis of diseases. Expected benefit must exceed recognizable risks. Serious predictable risks should be avoided. Only well-designed studies are ethically appropriate. Study protocols must be evaluated by ethics committees (institutional review boards) and reviewed by experts in pediatric issues. Informed consent or assent must be obtained from the child participant and informed consent from the legal representative.
Detailed operational guidelines for clinical investigations of medicinal products in the pediatric population are provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): 8
Once the IRB has approved a properly designed study, the task of obtaining consent or assent from children and their parents arises. The latest version of the Declaration of Helsinki13 suggests that for a legally incompetent minor, the investigator must obtain informed consent from the child’s legally authorized representative in accordance with applicable law. Even a legally incompetent minor may be able to give assent to decisions about participation in research, and in such cases the investigator must obtain that assent in addition to the consent of a legally authorized representative.
The informed consent and assent process for including children in biomedical research should include:
In general, WCCT Global believes that the consent of both parents should be sought prior to enrolling a child in a biomedical research project.
The case of utilizing long-term topical steroids in children can be used to demonstrate an ethical gray area pertaining to both therapeutics and clinical research. Long-term topical steroid use is the cornerstone for two very important conditions often encountered in children.
Long term systemic exposure to steroids has many endocrine, metabolic and local associated adverse events. A possible reduction in growth velocity, suppression of the hypothalamic-pituitary adrenal axis, effects upon bone structure and bone mass, weight gain and Cushing’s syndrome cause the most concern by doctors and parents following oral inhalation of steroids. Reduction in growth velocity and skin thinning cause the most concern to both Physicians and parents following long term topical steroid application.
Since the potential impact on growth velocity and linear growth is common to both routes of steroid administration in the asthma and eczema. This concern expressed by physicians and parents can lead to under-prescribing by physicians and even non-adherence to treatment (prescription not filled or skipped doses) by the child’s parents. Yet, until recently, no long -term studies have been documented looking at the effect of topical steroids on growth. Therefore, this concern has been mainly fueled by medical anecdote suggesting a negative effect of topical steroids on growth velocity or a few short-term studies demonstrating that topical steroids were “growth-neutral”. Physicians and parents have been waiting for more conclusive information on the potential of long term topical steroid’s effect on growth in order to provide a higher level of comfort that children will reach their potential height even while adequately treating their eczema or asthma.
Recently, Rao et al, have published their results of a retrospective, case controlled, study in prepubertal children with:
Prepubertal children with Type I Diabetes Mellitus (a chronic medical condition known not to effect linear growth in children) were followed concurrently and served as a comparative control group.
Data were collected retrospectively from the case notes and growth charts of patients attending pediatric asthma, dermatology and diabetic clinics retrospectively. The data collected included demographic data, date of diagnosis, date of start of treatment, regular height and weight measurements and disease control. In addition for children with asthma, type and dose of inhaled steroid and number of short courses of oral steroid was recorded. In children with eczema, data on type and strength of topical steroid was collected. In children with diabetes, regular insulin dose and HbA1c was documented. Height was measured using stadiometer by qualified nurses in the pediatric outpatient clinic. No formal pubertal assessment was made. The proportion of children aged nine years and below who enter puberty is very small.
The inhaled steroids used were beclomethasone dipropionate (strength 200 to 800 micrograms twice daily), Fluticasone propionate (strength 100 to 375 micrograms twice daily), Seretide (strength 100 to 300 micrograms twice daily). The dose was set based on the age and severity of the child following the British Thoracic guidelines for the management of asthma in children. The disease control, as assessed by spirometry findings, varied from good, moderate to poor control.
Topical steroids used were Hydrocortisone in the strength 0.1 to 1% (Iow potency), Clobetasone butyrate in the strength 0.05% (moderately potent), Betamethasone Valerate in the strength 0.1% to 0.25% (highly potent), Hydrocortisone Butyrate in the strength 0.1 % (highly potent) or various combinations. The strength of topical steroid depends on the age of the child and the severity of eczema. The combination of steroids was used in many children. The milder steroid was applied on the face and the higher potency steroid was applied on to the effected areas in the rest of the body.
Height velocity was calculated and expressed as height velocity standard deviation score (HVSDS) using the formula;
Height velocity SD score = Height velocity – mean height velocity for age
SD of height velocity for age
Mean HVSDS of all the three groups were subsequently compared.
|Gender ratio (M:F)||33:8||26:16||22:21|
All statistical comparisons between groups (Asthma vs. DM, Eczema vs. DM and Asthma vs. Eczema) were not significant (p>0.2).
This observed neutral effect on growth following orally inhaled and topically administered steroids is further supported by a meta-analysis incorporating 21 studies on 810 patients by Alien et al21 which showed that inhaled beclomethasone dipropionate therapy has no effect on growth in asthma. Also, Balfour-Lynn20 studied 66 patients for a period of 13.1 years and concluded that inhaled steroids administered to 26 children in a dosage up to 600mcgm/ day of beclomethasone dipropionate did not affect growth.
Although clinicians, parents and clinical investigators may be encouraged by these results which will eliminate one major hurtle for children who require topical steroids to treat their asthma or eczema much more supportive research remains to be carried out in order to enable safe use of many other drugs for children of all ages. This will surely require the combined efforts of pediatricians, clinical pharmacologists, researchers, manufacturers, medical societies and regulatory agencies to move pediatric trials forward with the necessary speed and care.
The staff at WCCT Global has extensive experience working with the development of new medicines for various diseases of childhood, having successfully carried out numerous pediatric trials as both an investigational site and a CRO managing pediatric studies at several sites. WCCT Global has studied both topical and systemic agents and has also been a Phase II/III investigational site for vaccines and allergy & asthma compounds in development. WCCT Global leverages their knowledge and experience in this therapeutic area to strategically help their clients. Additionally, WCCT Global is strategically based in a densely populated area of 8 million people found throughout the Southern California region and thus has access to a diverse set of patient populations.