Pediatric clinical trials: damned if you do, damned if you don’t
Drug regulators are in a quandary. On the one hand, they’d rather spare children from being used as test subjects in clinical trials. On the other hand, recent developments show an urgent need for pediatric testing.
There have been recent reports of adverse side effects, some of them fatal, attributed to OTC drugs for children. These concerned seemingly innocuous cough and cold medications containing active ingredients such as pseudoephedrine, paracetamol [1,2], and camphor [3]. But prescription drugs for children`s ailments such as asthma and ADHD are incriminated as well.
This brought to light how very little we actually know about pediatric pharmacology.
The problem lies with the fact that many drugs with well-established efficacy and safety profile have only been tested in adults. With an aging population and low birth rates in developed countries, the pediatric drug market is not really top priority for pharmaceutical industries. Very little money is allocated for pediatric R&D. Pharmacological results were simply extrapolated to pediatric population as “miniature adults.”
The issue is compounded by lack of test subjects. Very few parents in developed countries would ever consent that their children be enrolled in a clinical trial. Most pharmaceutical companies turn to developing countries for testing. Although there are strict guidelines regulating pediatric testing, there are still concerns about adherence to GCP in those countries.
The regulators are now scrambling to come up with solutions to plug this knowledge gap on pediatric drugs.
Last year, the US passed the Best Pharmaceuticals for Children Act 2007 and an amended version (2007) of the 2003 Pediatric Research Equity Act. The Acts empowered the US FDA to require drug companies to test new drugs on children before approval [4]. However, there is still a lack of knowledge on drugs approved before 2003.
In Europe, the EMEA is requiring a pediatric investigation plan for all new drug applications starting July 2008 (unless a non-pediatric use waiver is justified). In addition, it is funding research on off-patent drugs as well as looking into pediatric clinical data that may not have been previously published [5, 6].
In the meantime, millions of children need medications while drugs against cancer, infections, asthma, high blood pressure and hyperactivity currently available are waiting to be tested for pediatric use. Do we use these drugs or not ? Quandary for doctors and parents as well.
Damned if you do. Damned if you don’t.
References:
1. Wingert WE, Mundy LA, Collins GL, Chmara ES. Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children. J Forensic Sci. 2007 Mar;52(2):487-90.
2. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications–two states, 2005. Morb Mortal Wkly Rep. 2007 Jan 12;56(1):1-4.
3. Press Release, NYC Department of Health. January 17, 2008. Health department warns parents to keep camphor products away from children.
4. US FDA, Pediatric Drug Development. Retrieved 27 Jan 2008.
5. Sinha G.J. EU law mandates drug testing in children. J. Natl Cancer Inst. 2008 Jan 16;100(2):84-5.
6. EMEA Press Release Paediatric Committee (PDCO), 25 Jan 2008.
Clinical predictors of severe illness in neonates
In a multinational study, researchers evaluated 3177 aged 0-6 days old and 5712 infants aged 7 to 59 days old admitted to healthcare centers in Bangladesh, Bolivia, Ghana, India, Pakistan, and South Africa. They recorded the clinical signs and symptoms and evaluated the “sensitivity, specificity, and odds ratio (OR) for each symptom and sign individually and combined into algorithms to assess their value for predicting severe illness.” Jaundice was excluded in the analysis.
Results showed 12 independent clinical predictors of severe illness that would indicate the need for hospitalization in the 0–6 days age-group. These clinical signs are as follows:
1. History of difficult feeding
2. History of convulsions
3. Movement only when stimulated
4. Fast respiratory rate (≥60)
5. Severe chest indrawing
6. Pyrexia (>37.5 °C)
7. Low body temperature (<35.5)
8. Lethargy
9. Prolonged capillary refill
10. Grunting
11. Cyanosis
12. Stiff limbs
These predictors were also shown to be sensitive in the older age group.
To simply decision-making for primary care practitioners, the number of clinical signs indicative of the need for hospitalization was reduced, taking into account only the first seven in the list. This reduction did not significantly reduce the sensitivity of the check list.
Source:
Clinical signs that predict severe illness in children under age 2 months: a multicentre study. The Young Infants Clinical Signs Study Group. The Lancet 2008; 371:135-142.
Passive smoking and allergies in children
Study design and objective
The aim of this prospective birth cohort study was to investigate the relationship between in utero and postnatal exposure of children to environmental tobacco smoke and IgE-sensitization.
Study population and primary end-points
The study was conducted in Stockholm, Sweden and followed-up families with young children. A total of 4089 families participated and answered questionnaires which survey smoking habits in the family and allergic symptoms in the children. Questionnaires were completed when the children was aged 2 months, 1, 2 and 4 years old. Blood tests for IgE antibodies to common food and inhalant allergens were performed at age 4 years.
Results
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Early exposure of children to environmental tobacco smoke was significantly associated with increased risk for sensitization to mold, cat, horse, and food allergens at 4 years but not to seasonal allergens such as pollens.
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A dose-response relationship for passive smoking exposure at 2 months and IgE sensitization was observed.
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IgE sensitization was strongest in cases of biparental smoking, followed by maternal smoking, and then paternal smoking.
Weakness of the study
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There is a difficulty in distinguishing the effects of prenatal from postnatal exposure to tobacco smoke.
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There might be bias due to the common and early use of daycare facilities in
Sweden. 75% of the study cohort was at daycare centers by age 2.
The study was funded by the Swedish Heart and Lung Foundation, Stockholm County Council, the Gillbergska Foundation and the Swedish Asthma and Allergy Foundation, the Swedish Foundation for Health Care Sciences and Allergy Research, and the Swedish Research Council.
Source:
Baby’s First Solid Food: Later is Not Necessarily Better
More and more mothers are putting off the introduction of first solid food to infants out of fear of food allergies and celiac disease. Two recent reports indicate that this delay is actually unwarranted and can lead to health problems. In a recent review, Guandalini reports that not only early but also “late (7 months or after) first explosure to gluten may favor the onset of celiac disease in predisposed individuals” [1]. Too early and too late gluten introduction can also result “in a significantly higher risk of the appearance of islet cell immunity,” a condition that can lead to type-1 diabetes.
In another study, German researchers did not find any association between the time of solid food introduction, the type of food, and the incidence of eczema in a cohort of 4753 infants. The results of the study indicate that „neither a delayed introduction of solids beyond the fourth month nor a delayed introduction of the most potentially allergenic solids beyond the sixth month of life“ can prevent eczema in infants [2].
Based on recent evidence, introduction of solid foods to babies should occur between 4 and 6 months and only as complementary food to breast milk. Breasfeeding during the introduction of gluten can delay the onset of celiac disease [1].
Sources:
[1] Issues in Complementary Feeding (2007). Nestle Nutr Workshop Ser Pediatr Program 60: 139-155.
[2] Journal of Pediatrics 151:352-358 (October 2007)