Studies supporting the approval of the majority of drugs used to treat attention-deficit/hyperactivity disorder (ADHD) in children were not designed to demonstrate long-term safety and efficacy of the drugs or detect rare adverse events (AEs), new research shows.
Investigators at Boston Children's Hospital in Massachusetts found that the majority of studies carried out by sponsors prior to market approval of their ADHD drug were either too small, too short, or both to extrapolate meaningful clinical gains during longer-term follow-up of children receiving drugs for ADHD.
"There is a disconnect between the way these drugs are approved in that they are tested in small numbers of patients over short periods of time vs the way the drugs are used, which is in large numbers of patients for many years," senior author Kenneth Mandl, MD, MPH, professor of pediatrics, Harvard Medical School and the Children's Hospital Informatics Program, told Medscape Medical News.
"So this has large implications about the way we think about the safety and efficacy of these drugs. It's also impossible to assess the kind of outcomes [from ADHD trials] that parents and physicians would be most interested in, including the impact these drugs may have on educational performance or cognitive and emotional development."
The study was published online July 9 in PLoS One.
For the study, the authors identified all ADHD medications approved by the US Food and Drug Administration (FDA) and analyzed data from clinical trials used by the FDA to evaluate the drugs' clinical efficacy and safety.
Sponsors carried out 32 clinical trials in all for the approval of 20 different ADHD drugs. These 20 drugs represent 10 different active ingredients, with individual products differing in formulation and delivery systems. Only 3 out of the 20 drugs have been discontinued since their FDA approval.
The median number of participants studied per drug was 75, but 11 drugs were approved after being studied in fewer than 100 participants, and 14 of the drug trials included fewer than 300 individuals. (Some of the 11 drugs were also included in trials that included fewer than 300 individuals).
The median length of the trial prior to approval was 4 weeks. Again, however, more than three quarters of the trials were carried out for less than 6 months, and more than one third were conducted for less than 4 weeks.
"The take-home is that overall, half of these drug trials included fewer than 100 participants, which is a striking number, as it is indeed quite small," lead author Florence Bourgeois, MD, MPH, told Medscape Medical News.
The other "striking" finding, she added, was that the median trial length was only 4 weeks, clearly not long enough to evaluate patient-centered outcomes, such as the impact of ADHD therapy on cognitive and developmental parameters.
Investigators also found that the FDA had approved 7 drugs without sponsors submitting any clinical trial data on the use of the drug for the treatment of ADHD in a pediatric population.
All 7 of these drugs had been previously approved by the FDA for other conditions, such as obesity.
The FDA also asked sponsors of 6 different drugs to provide additional postmarketing trial data, but only 2 complied.
It is important to carry out postmarketing trials following a drug's approval in order to monitor larger groups of patients for rare AEs that would not be detected in limited clinical trials, the authors note.
More Recent Approvals
Drugs approved for the treatment of ADHD in the last decade were subject to somewhat more thorough scrutiny, the researchers note.
Of the 6 drugs approved since 2004 for the treatment of ADHD, the median number of participants studied per drug was 259.
On the other hand, almost three quarters of participants were still only studied for less than 6 months.
With the more recently approved drugs, the median trial length prior to receiving FDA approval was 8 weeks.
In addition, the researchers point out that none of the drugs approved for ADHD met recommendations from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) for testing and approval for drugs used to treat non-life-threatening chronic conditions.
As the ICH suggests, AEs first occur and are most frequent during the initial months of treatment.
To capture these AEs, the ICH recommends that between 300 and 600 patients be treated for at least 6 months prior to market availability of any drug.
Alternatively, the ICH indicates that at least 100 patients should be exposed to a drug for at least 12 months to capture AEs.
Three drugs — Daytrana (Noven Pharmaceuticals, Inc), Focalin (Novartis Pharmaceuticals Corporation), and Concerta (Janssen Pharmaceuticals, Inc) ― did meet ICH requirements that at least 300 participants be exposed to the drug for 6 months prior to marketing the drug.
Both Daytrana and Focalin also complied with the ICH recommendation to study at least 100 participants in their drug trials for 12 months.
"By in large, we do know that these drugs work, given how long they have been on the market and the number of patients who have taken them, at least in the short term," Dr. Bourgeois said.
"But there is some debate over how effective they are in the long term, and it's important that parents are aware of what is known about the benefits of these drugs and what is not known so they can make the right decision about the drug for their child."
Asked by Medscape Medical News to comment on the study, Adelaide Robb, MD, professor of psychiatry and pediatrics, George Washington University, Washington, DC, felt that the study was "alarmist" and, actually, "inappropriately alarmist."
"Most of the medications that we are talking about for ADHD have been studied long term and extensively in children," Dr. Robb insisted.
"So when you are prescribing Daytrana, for example, that's the same methylphenidate molecule that's been in all of the other Ritalin [Novartis Pharmaceuticals Corporation] trials. All investigators want to see is whether the liquid preparation or the under-the-tongue preparation or the through-the-skin preparation gets absorbed, and does it still work? If the answer is yes, the long-term safety and toxicity issues have already been asked and answered."
Dr. Robb also felt that pediatric ADHD studies lasting 6 months or, better still, 12 months do give physicians a good idea of what the short- and median-term side effects of a drug are.
"Research in children is important," Dr. Robb concluded. "Finding out more information about long-term safety is also important, and we need to dedicate more NIH [National Institutes of Health] dollars to doing that. So I think what this study is, is a message back to the federal government to give more money to the NIH to do long-term studies of medication in children."
The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. None of the study authors have disclosed any relevant financial relationships. Dr. Robb reports that she has received research support from a number of pharmaceutical companies for clinical trials involving ADHD drugs.
PLos One. Published online July 9, 2014. Full text
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Cite this: ADHD Drugs Not Tested for Safety, Efficacy Over Time - Medscape - Jul 17, 2014.