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.
Fast food and CVD: where`s the connection?
Be it burgers, pizza or fries, what is it with fast food diet that makes it a major CVD risk factor? In the recent issue of the Journal of the American College of Cardiology, researchers published the answers [1].
Consumption of high-calorie, low-nutrient food causes a sudden increase in blood glucose and triglyceride levels and results in a state known as postprandial dysmetabolism. These after-meal spikes in sugar and free fatty acids “overwhelm the body’s ability to handle the surge, resulting in a flooding of the Kreb’s cycle and the production of superoxide anions. The postprandial production of these free radicals acutely triggers atherogenic changes, such as increases in LDL oxidation, sympathetic tone, vasoconstriction, and thrombogenicity [2].”
At the end of the scale, traditional Mediterranean or Okinawan diets (consisting of lean protein, fish oil, whole grains, vegetables and low to moderate amounts of alcohol among others) has been shown to be anti-inflammatory and to lower CVD risks [1].
References:
1. O’Keefe JH, Gheewala NM, O’Keefe JO, 2008. Dietary Strategies for Improving Post-Prandial Glucose, Lipids, Inflammation, and Cardiovascular Health. J Am Coll Cardiol, 2008; 51:249-255, doi:10.1016/j.jacc.2007.10.016
2. O`Riordan M. Big Macs and Whoppers: Spikes in after-meal glucose and lipid levels lead to inflammation and CVD. HeartWire 16 Jan 2008.
Symposium on Publishing Clinical Trials
What: A one-day symposium jointly organized by the Institute of Clinical Research and the European Medical Writers`Association.
Theme: Publishing Clinical Trials: Ethics and the Pharmaceutical Industry.
When and where: 27 February 2008, Novotel Hammersmith, 1 Hammersmith International Centre, London.
“This symposium will be presented by a panel of experts including medical writers, journal editors, academics and pharmaceutical industry managers. Topics will include publication policy, ghostwriting, fraud and other ethical issues of publishing clinical trials.”
Details and registration at www. icr-global.org
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.
ENHANCE trial update: no beneficial effects on CA IMT from ezetimibe
The much-awaited results of the “Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression” (ENHANCE) trial are finally out – and they are a huge disappointment.
ENHANCE is an international 2-year, randomized, double-blind, controlled trial which compared the combination of ezetimibe and simvastatin to simvastatin monotherapy.
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor routinely used in the management of atherosclerosis. The newcomer ezetimibe is a specific cholesterol absorption inhibitor and the 2 drugs supposedly act as complementary agents that can have beneficial effects on the carotid artery intima-media thickness (CA IMT) of atherosclerosis patients. The trial was conducted in 720 patients with heterozygous familial hypercholesterolemia. The primary end point was mean change in the IMT measured at 3 different sites in the carotid arteries [1].
The trial results showed no significant difference in the mean IMT change between patients treated with ezetimibe/simvastatin 10/80 mg vs patients treated with simvastatin 80 mg alone. There was also no significant difference in treatment-related adverse events in both treatment groups. However, ezetimibe was associated with a larger reduction in LDL cholesterol [2].
References:
1. Kastelein et al., 2005. Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. American Heart Journal 149 (2): 234-239.
2. Hughes, S. 2008. ENHANCE results yield disappointment for ezetimibe. Heartwire 14 Jan 2008.
Photo credit
Bisphenol A contamination in plastic bottles
Plastic water bottles were taken off the shelves in Canada last month and caused concerns worldwide. The offending substance in the bottles is bisphenol A (BPA), an endocrine-disrupting chemical (EDC). In the latest issue of Toxicology Letters, American researchers published the results of their research on the health risks of BPA [1].
BPA is “an estrogenic high-production chemical used primarily as a monomer for the production of polycarbonate and epoxy resins.” Bioactive BPA is released from polycarbonate bottles at rates ranging from 0.20ng/h to 0.79ng/h. There is no significant difference in the BPA migration rates in new and used bottles at room temperatures. At 100°C (e.g. contact with boiling water), the migration rates increased by up to 55-fold. The estrogenic bioactivity of the BPA-like immunoreactivity released into the water samples was confirmed using an in vitro assay of rapid estrogen signaling and neurotoxicity in developing cerebellar neurons.
Based on these findings, the following conclusions can made:
- Food and beverages which come in contact with epoxy resins or polycarbonate plastic containers may be contaminated by bioactive BPA.
- Human exposure to BPA is actually widespread and the substance should therefore be as a contributing source to the total “EDC-burden”.
This is not the first study to investigate the migration of PBA. However, there are differing opinions whether the amounts released are high enough to present a health risk. Aside from plastic bottles, other BPA sources are polycarbonate dental products and food packaging [2].
Sources:
1 Le HH, Carlson EM, Chua JP, Belcher SM., 2008. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett. 2008 Jan 30;176(2):149-56. Epub 2007 Nov 19.
2 Howdeshell KL, Peterman PH, Judy BM, Taylor JA, Orazio CE, Ruhlen RL, Vom Saal FS, Welshons WV., 2003. Bisphenol A is released from used polycarbonate animal cages into water at room temperature. Environ Health Perspect. 2003 Jul;111(9):1180-7.
The First Rapid Blood Test for MRSA is in the Market
In recent years, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection have been on the rise. This has especially become a problem in hospitals where MRSA infections have become synonymous to healthcare-associated infections.
S. aureus is a very common bacterial species that causes pimples and mild skin and wound infections. However, years of antibiotic use gave rise to strains which are resistant to the antibiotic methicillin as well as to other drugs. The MRSA strains can cause life-threatening conditions such as sepsis, infections of surgical sites, and pneumonia.
The US FDA has recently approved the first quick test to identify MRSA in the blood. Using molecular methods, the BD GeneOhm StaphSR Assay can detect genetic material from the common, less dangerous methicillin-sensitive S. aureus (MSSA) as well as the drug-resistant deadly MRSA strains [1, 2]
Early detection of MRSA infections is crucial in their treatment and management. Using standard diagnostic laboratory tests, it takes 2 days to identify MRSA in blood samples. With the new rapid test, results are available within 2 hours. This is especially good news to the public health community which had to deal with the rapid rise in the incidence of MRSA infections in hospitals and clinics. Immunocompromised patients are especially susceptible.
The BD GeneOhm StaphSR test is manufactured by BD Diagnostics, a subsidiary of BD of Franklin Lakes, N.J.
[1] FDA News, 2 Jan 2008. FDA Clears First Quick Test For Drug-Resistant Staph Infections.