The finding -- from a systematic review of anti-epileptic drugs -- has important implications for the design of clinical trials in children, according to Philippe Ryvlin, M.D., Ph.D., of the Hospices Civils de Lyon, and colleagues.
Failing to take the higher placebo effect into account might result in falsely negative results, Dr. Ryvlin and colleagues said online in PLoS Medicine.
The finding is also an illustration of the lack of pediatric clinical trials, commented to Terry Klassen, M.D., of the University of Alberta, and colleagues in an accompanying perspective article.
"The lack of trial evidence goes beyond neurological diseases to other childhood areas, such as pediatric cardiology, neonatology, pediatric intensive care, and oncology," Dr. Klassen and colleagues wrote.
The current study and research like it, Dr. Klassen and colleagues said, is "important to inform the design and reporting of pediatric trials."
Dr. Ryvlin and colleagues noted that pivotal trials in children with epilepsy have almost always been done as phase IV studies, after a drug has been approved for use in adults.
However, "unpredictable differences may exist in drug metabolism and treatment response between children and adults," they said. For instance, the clearance of modern anti-epileptic drugs is up to 1.7 times higher in children than in adults.
To understand the issue better, Dr. Ryvlin and colleagues searched three major electronic databases, as well as several other possible sources, for randomized clinical trials of anti-epileptic drugs in both children and adults.
All told, they found 32 studies, five in children, that evaluated five different drugs: gabapentin (Neurontin), levetiracetam (Keppra), lamotrigine (Lamictal), oxcarbazepine (Trileptal), and topiramate (Topamax).
The primary endpoint of the analysis was the proportion of patients with a 50% or greater reduction in seizure frequency during treatment, compared with baseline.
In the 32 studies, the average duration of the treatment period was 15 weeks.
Except for trials of lamotrigine, the average dose for children and adults differed -- higher for gabapentin, levetiracetam, and oxcarbazepine, and lower for topiramate, the researchers found.
- For children on treatment, compared with those on placebo, the relative risk of being a 50% responder was 1.91, with a 95% confidence interval from 1.54 to 2.37.
- For adults on treatment, compared with those getting placebo, the relative risk of being a 50% responder was 2.9, with a 95% confidence interval from 2.47 to 3.41.
- The ratio of the relative risks was 0.67, implying a difference between children and adults that was significant at P<0.007.
The difference was mainly the result of a higher placebo effect in the children, the researchers found.
A logistic regression analysis showed that the mean 50% responder rate in children receiving placebo was 19%, compared with 9.9% in adults. The difference was significant at P<0.001.
On the other hand, 37.2% of children responded to the drugs, compared with 30.4% of adults, which was not a significant difference, Dr. Ryvlin and colleagues.
The study was limited by the lack of randomized clinical trials in children with just one for each drug, the researchers said. It is also possible that there was significant heterogeneity both among and within trials, they said.
There might also have been selection bias -- since there is reluctance to enroll children in trials, patients with more severe disease might have been over-represented, they said.
And it is not clear if the findings can be extended to other forms of epilepsy, they added.
|The study had no specific funding support. Dr. Ryvlin reported financial links with Cyberonics, Eisai, GSK, Janssen-Cilag, Novartis, Pfizer, Sanofi-Synthelabo, UCB, and Valeant.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
PLoS MedicineSource Reference: Rheims S, et al "Greater response to placebo in children than in adults: A systematic review and meta-analysis in drug resistant partial epilepsy" PLoS Med 2008; 5(8): e166.
PLoS MedicineSource Reference: Klassen TP, et al "Children are not just small adults: The urgent need for high-quality trial evidence in children" PLoS Med 2008; 5(8): e172.