A Black-Box Warning for Antidepressants in Children?
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《新英格兰医药杂志》
The editors asked two members of the Psychopharmacologic Drugs and Pediatric Advisory Committees of the Food and Drug Administration to comment on the committees' recent recommendations regarding the use of antidepressant medications in children and adolescents.
Their responses follow.
On September 14, 2004, a Food and Drug Administration (FDA) joint advisory committee voted 15 to 8 to recommend that a "black-box" warning label be required for antidepressant drugs, indicating that they increase the risk of suicidal thinking and behavior ("suicidality") in pediatric patients. Although, as an epidemiologist and general pediatrician, I do not have clinical experience caring for depressed patients, after reviewing the evidence, I strongly favored the black-box warning.
During consideration of the proposed labeling change, the committee heard a number of presentations summarizing evidence that suicidality in children and adolescents may be increased by the newer antidepressant drugs, primarily selective serotonin-reuptake inhibitors. The most convincing evidence came from an FDA analysis of randomized trials. Most of these trials had been conducted by the drug manufacturers under the Best Pharmaceuticals for Children Act, which provides companies an additional six months of patent protection for their product if they do pediatric studies. These studies need not be published and need not be of high quality. In fact, we heard that because these medications are already widely prescribed "off-label" and patents may be close to expiration, sponsors may have more incentive to do the studies quickly than to do them well. To facilitate analysis of the patchwork of pediatric studies, the FDA obtained narratives of adverse-event reports from the trials and contracted with experts on suicide at Columbia University to review them. The Columbia staff members, who were unaware of the treatment-group assignments, were asked to determine whether the adverse events represented suicidality. FDA staff members then combined the results into a meta-analysis.
The results were striking. When all the pediatric trials were pooled, the rate of definite or possible suicidality among children assigned to receive antidepressants was twice that in the placebo group. (The summary risk ratio was 2.19; 95 percent confidence interval, 1.50 to 3.19.) Although the FDA staff did not provide this information to the committee, according to my own calculations, such a dramatic result would be expected to occur by chance only 1 time in 20,000 (P=0.00005).
Nonetheless, some FDA staff and committee members expressed reservations about the data used for this analysis. For example, there was a relatively small number of events, the trials had not been designed to evaluate suicidality, and the methods of ascertainment and classification of the events in the various trials were not uniform. To me, however, these concerns only made the results more compelling. Inadequate sample size and misclassification of outcomes make it more — not less — difficult to detect differences between groups in randomized, blinded trials. The fact that an association emerged from the meta-analysis with a P value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing.
Inferences from the randomized trials were supported by public testimony from people who believed that antidepressant drugs had caused their loved ones to commit suicide (or, in some cases, homicide). Several of these cases involved patients who had shown no hint of suicidality before beginning treatment with the drugs and who had been given these drugs for indications other than depression, including migraine headaches, nail biting, anxiety, and insomnia.
Several committee members spoke in favor of the antidepressants, citing either their own clinical experience or the Treatment for Adolescents with Depression Study (TADS),1 a recently published randomized, double-blind study of fluoxetine for major depression in adolescents, which the committee reviewed in detail. However, others and I found the evidence of efficacy much less convincing than the evidence of harm. In reviewing TADS, we were struck by the small size of the difference between fluoxetine and placebo as compared with the effect of placebo alone. For example, after 12 weeks, the average decrease in the Childhood Depression Scale–Revised (scores on which were around 60 of a possible 113 at baseline in both groups, with higher scores indicating more severe depression) was 19.4 points with placebo, as compared with 22.6 points with fluoxetine (see Figure). It is easy to see why the personal experience of clinicians and patients would lead them to believe the drug to be effective, since they would have no way of knowing that more than 85 percent of the benefit they observed would also have occurred with placebo.
Figure. Mean Changes in Score on the Childhood Depression Scale–Revised in the Treatment for Adolescents with Depression Study.
Data are from March et al.1 The average scores at baseline, out of a possible 113, were 58.9 in the fluoxetine group and 61.2 in the placebo group. Higher scores indicate more severe depression.
Randomized trials other than TADS have had less favorable results. The FDA indicated that only 3 of 15 trials of antidepressant use in children with depression had found a statistically significant benefit. The agency also provided us with a meta-analysis2 that showed that the estimated efficacy of antidepressants in children was minimal and likely to have been overestimated, because published studies have much more favorable results than unpublished studies. Thus, both clinical experience and published trials are likely to lead to inflated estimates of the efficacy of these drugs.
The committee members agreed that there are wide gaps in our knowledge about antidepressants. Perhaps the most important relate to their medium-term and long-term safety and efficacy. The FDA's meta-analysis suggested that the new antidepressants double the risk of suicidality, from about 2.5 percent to 5 percent, in trials lasting two or three months. But what happens if you take them for a year? Does a 5 percent risk over the course of three months become a 20 percent risk over the course of a year, or does the benefit–risk balance improve over time? Does the increase in the rate of suicidality translate into an increase in the rate of completed suicide? Do additional adverse effects occur after treatment with the medications is stopped? Are there important differences among the drugs in this class? What age groups are at risk? It seems unlikely that the drugs suddenly become safe after the patient's 18th birthday. Currently, no one knows the answer to any of these questions.
There was also agreement that the experience with antidepressants illustrates serious deficiencies in the implementation of the Best Pharmaceuticals for Children Act U.S. consumers, through higher drug prices buoyed by extended market exclusivity, are paying a high price for pediatric studies that may be poorly conducted and selectively disseminated. The public is the loser, both because the availability of generic versions of the drugs is then delayed and because poor science and selective publication can lead to false conclusions about pediatric safety and efficacy. If these studies are to provide value, the requirement to do them must be changed to a requirement to do them well. Extended exclusivity should be granted only if the studies conducted in order to receive it are judged to be of high quality by independent peer review and if their results are disseminated in a timely manner.
Finally, this controversy over the use of antidepressants in children illustrates the need for a more sophisticated approach to evaluating harms and efficacy than simply seeing whether they are statistically significant at a P value of less than 0.05. Regardless of the P value, no psychotropic drug is free of potential negative effects. The best available estimates of the magnitude and nature of the effects of the drugs must be discussed with patients and families, so that they can make an informed decision about treatment. My hope is that the FDA will follow the recommendation of the advisory committee and require a black-box warning — and that doing so will make these discussions more likely to take place.
Source Information
From the Departments of Epidemiology and Biostatistics and Pediatrics, University of California San Francisco, San Francisco.
References
March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292:807-820.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-1345.(Thomas B. Newman, M.D., M)
Their responses follow.
On September 14, 2004, a Food and Drug Administration (FDA) joint advisory committee voted 15 to 8 to recommend that a "black-box" warning label be required for antidepressant drugs, indicating that they increase the risk of suicidal thinking and behavior ("suicidality") in pediatric patients. Although, as an epidemiologist and general pediatrician, I do not have clinical experience caring for depressed patients, after reviewing the evidence, I strongly favored the black-box warning.
During consideration of the proposed labeling change, the committee heard a number of presentations summarizing evidence that suicidality in children and adolescents may be increased by the newer antidepressant drugs, primarily selective serotonin-reuptake inhibitors. The most convincing evidence came from an FDA analysis of randomized trials. Most of these trials had been conducted by the drug manufacturers under the Best Pharmaceuticals for Children Act, which provides companies an additional six months of patent protection for their product if they do pediatric studies. These studies need not be published and need not be of high quality. In fact, we heard that because these medications are already widely prescribed "off-label" and patents may be close to expiration, sponsors may have more incentive to do the studies quickly than to do them well. To facilitate analysis of the patchwork of pediatric studies, the FDA obtained narratives of adverse-event reports from the trials and contracted with experts on suicide at Columbia University to review them. The Columbia staff members, who were unaware of the treatment-group assignments, were asked to determine whether the adverse events represented suicidality. FDA staff members then combined the results into a meta-analysis.
The results were striking. When all the pediatric trials were pooled, the rate of definite or possible suicidality among children assigned to receive antidepressants was twice that in the placebo group. (The summary risk ratio was 2.19; 95 percent confidence interval, 1.50 to 3.19.) Although the FDA staff did not provide this information to the committee, according to my own calculations, such a dramatic result would be expected to occur by chance only 1 time in 20,000 (P=0.00005).
Nonetheless, some FDA staff and committee members expressed reservations about the data used for this analysis. For example, there was a relatively small number of events, the trials had not been designed to evaluate suicidality, and the methods of ascertainment and classification of the events in the various trials were not uniform. To me, however, these concerns only made the results more compelling. Inadequate sample size and misclassification of outcomes make it more — not less — difficult to detect differences between groups in randomized, blinded trials. The fact that an association emerged from the meta-analysis with a P value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing.
Inferences from the randomized trials were supported by public testimony from people who believed that antidepressant drugs had caused their loved ones to commit suicide (or, in some cases, homicide). Several of these cases involved patients who had shown no hint of suicidality before beginning treatment with the drugs and who had been given these drugs for indications other than depression, including migraine headaches, nail biting, anxiety, and insomnia.
Several committee members spoke in favor of the antidepressants, citing either their own clinical experience or the Treatment for Adolescents with Depression Study (TADS),1 a recently published randomized, double-blind study of fluoxetine for major depression in adolescents, which the committee reviewed in detail. However, others and I found the evidence of efficacy much less convincing than the evidence of harm. In reviewing TADS, we were struck by the small size of the difference between fluoxetine and placebo as compared with the effect of placebo alone. For example, after 12 weeks, the average decrease in the Childhood Depression Scale–Revised (scores on which were around 60 of a possible 113 at baseline in both groups, with higher scores indicating more severe depression) was 19.4 points with placebo, as compared with 22.6 points with fluoxetine (see Figure). It is easy to see why the personal experience of clinicians and patients would lead them to believe the drug to be effective, since they would have no way of knowing that more than 85 percent of the benefit they observed would also have occurred with placebo.
Figure. Mean Changes in Score on the Childhood Depression Scale–Revised in the Treatment for Adolescents with Depression Study.
Data are from March et al.1 The average scores at baseline, out of a possible 113, were 58.9 in the fluoxetine group and 61.2 in the placebo group. Higher scores indicate more severe depression.
Randomized trials other than TADS have had less favorable results. The FDA indicated that only 3 of 15 trials of antidepressant use in children with depression had found a statistically significant benefit. The agency also provided us with a meta-analysis2 that showed that the estimated efficacy of antidepressants in children was minimal and likely to have been overestimated, because published studies have much more favorable results than unpublished studies. Thus, both clinical experience and published trials are likely to lead to inflated estimates of the efficacy of these drugs.
The committee members agreed that there are wide gaps in our knowledge about antidepressants. Perhaps the most important relate to their medium-term and long-term safety and efficacy. The FDA's meta-analysis suggested that the new antidepressants double the risk of suicidality, from about 2.5 percent to 5 percent, in trials lasting two or three months. But what happens if you take them for a year? Does a 5 percent risk over the course of three months become a 20 percent risk over the course of a year, or does the benefit–risk balance improve over time? Does the increase in the rate of suicidality translate into an increase in the rate of completed suicide? Do additional adverse effects occur after treatment with the medications is stopped? Are there important differences among the drugs in this class? What age groups are at risk? It seems unlikely that the drugs suddenly become safe after the patient's 18th birthday. Currently, no one knows the answer to any of these questions.
There was also agreement that the experience with antidepressants illustrates serious deficiencies in the implementation of the Best Pharmaceuticals for Children Act U.S. consumers, through higher drug prices buoyed by extended market exclusivity, are paying a high price for pediatric studies that may be poorly conducted and selectively disseminated. The public is the loser, both because the availability of generic versions of the drugs is then delayed and because poor science and selective publication can lead to false conclusions about pediatric safety and efficacy. If these studies are to provide value, the requirement to do them must be changed to a requirement to do them well. Extended exclusivity should be granted only if the studies conducted in order to receive it are judged to be of high quality by independent peer review and if their results are disseminated in a timely manner.
Finally, this controversy over the use of antidepressants in children illustrates the need for a more sophisticated approach to evaluating harms and efficacy than simply seeing whether they are statistically significant at a P value of less than 0.05. Regardless of the P value, no psychotropic drug is free of potential negative effects. The best available estimates of the magnitude and nature of the effects of the drugs must be discussed with patients and families, so that they can make an informed decision about treatment. My hope is that the FDA will follow the recommendation of the advisory committee and require a black-box warning — and that doing so will make these discussions more likely to take place.
Source Information
From the Departments of Epidemiology and Biostatistics and Pediatrics, University of California San Francisco, San Francisco.
References
March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292:807-820.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-1345.(Thomas B. Newman, M.D., M)