How Informative Are Parent Reports of Attention-Deficit/Hyperactivity Disorder Symptoms for Assessing Outcome in Clinical Trials of Long-Acting Treatments? A Pooled Analysis of Parents’ and Teachers’ Reports
* Pediatric Psychopharmacology Research, Massachusetts General Hospital, Boston, Massachusetts
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. The validity of parent reports of children’s attention-deficit/hyperactivity disorder (ADHD) symptoms has been questioned, especially in clinical trials. Some advocate the exclusive use of teacher reports, maintaining that parent reports are not sensitive to changes in ADHD symptoms. This study compares the ability of parent and teacher reports to document change during clinical trials of long-acting treatments.
Methods. We conducted a literature search of Medline to identify any published clinical trials in pediatric ADHD that met the following criteria: 1) used a randomized design, 2) examined the efficacy of long-acting agents or standard formulations using 3-times-a-day dosing, and 3) used both parent and teacher reports of the same measure of ADHD symptoms as a study outcome. For each measurement of ADHD symptoms, we calculated effect sizes for parent and teacher reports.
Results. Three large, randomized, controlled clinical trials were identified (N = 1445 subjects). For every outcome for which teacher reports documented significant improvement, parent reports did also. Pooled analysis revealed a larger effect captured by the parent report relative to the teacher report.
Conclusion. Results suggest that parent reports are at least as sensitive to detecting change in ADHD symptoms as teacher reports in clinical trials that assess the efficacy of long-acting agents. These results suggest that parent reports are informative for detecting change during treatment of children with ADHD.
Key Words: ADHD • clinical trials • pooled analysis • long-acting treatments • parent reports
Abbreviations: ADHD, attention-deficit/hyperactivity disorder • MTA, Multimodal Treatment of ADHD • tid, 3 times a day • IR, immediate-release • MPH, methylphenidate • OROS, ostomotic-release oral system • SNAP, Swanson, Nolan, and Pelham questionnaire
Clinical trials in pediatric attention-deficit/hyperactivity disorder (ADHD) have traditionally relied on teachers’ reports to assess the outcome of participating youths. Although the reasons for this state of affairs are varied, perhaps the most important one stems from what had been the mainstream pharmacotherapeutic approach to the management of ADHD children, an approach that provided medication coverage for ADHD during school hours only.1,2 If children are not being treated after school or during school holidays, weekends, and school vacations, then parents cannot directly observe the therapeutic benefits of pharmacologic treatments, rendering parent reports uninformative for the assessment of outcome in clinical trials of youths with ADHD. This approach made it necessary to rely on teachers’ report to assess outcome of therapeutic trials of youths with ADHD.
In recent years, however, there has been an increasing recognition that ADHD is not only a school disorder but also a condition that can impair the functioning of the child in all aspects of life.3–5 For example, recent large-scale studies showed that children with ADHD were at high risk for impairments in multiple domains, including not only school functioning but also emotional, familial, cognitive, and interpersonal functioning.6 This was the case irrespective of gender (male or female) or ascertainment source (psychiatric or pediatric), emphasizing the ubiquitous impact that the disorder can have.6 The potential danger of untreated ADHD was underscored by work that showed that adolescents with ADHD were at increased risk for traffic accidents.4 These data generated a paradigm shift in the therapeutic approaches to ADHD that emphasized day-long treatment 7 days a week and year-round.7,8
This therapeutic shift is best reflected in the Multimodal Treatment of ADHD (MTA) study,9 which relied on 3-times-a-day (tid) administration of immediate-release methylphenidate (IR MPH) with the clear goal of covering the child’s full day, not only the school day. This paradigm shift is also reflected in the highly successful development of long-acting delivery systems for stimulant agents for the treatment of ADHD, with a clear goal of day-long coverage.
Because parents do in fact observe manifestation of their child’s illness through school-related activities performed at home and general behavior, this paradigm shift created a new environment in which parents are increasingly able to observe and monitor the treatment effects of psychotropic agents that are used in their children. Thus, they can witness changes that occur with the onset of medication and provide informative reports of such changes in a clinical trial setting. This state of affairs could conceivably create a new observational environment in which the parent could report adequately and sensitively on the improvement in ADHD symptoms that could inform the outcome of a clinical trial. However, empirical evidence that supports the notion that parents can identify and report treatment effects in youths with ADHD in a clinical trial setting are lacking.
The informativeness of parental reports in clinical trials of children with ADHD has important implications. Although desirable, teacher reports can be difficult to procure because of teachers’ own workload, multiple teachers’ attending to the same student, and the frequent breaks and vacations that break up the school year. In fact, considering the current public school schedule, a researcher would be hard-pressed to find an uninterrupted block of school time within which to conduct a comprehensive clinical trial of informative duration using teacher reports for an outcome measure. These constraints greatly limit drug development efforts in pediatric ADHD. Thus, if parental reports were to be found to be equally informative to those of teachers reports, then it would be very useful to researchers who conduct studies of children with ADHD and help bolster drug development efforts in this disorder.
This study evaluated empirically the informativeness of parents’ reports to assess outcome in clinical trials to treat children with ADHD with long-acting agents. To this end, a systematic literature search was conducted to evaluate studies that addressed these issues, providing data from large-scale clinical trials of stimulant medications in children with ADHD to compare parent reports on outcome relative to teacher reports. We hypothesized that parents’ reports would compare favorably with teachers’ reports in assessing the efficacy of long-acting pharmacologic treatments for ADHD in children.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a literature search of Medline to identify any published studies that met the following criteria: 1) used a randomized design, 2) examined the efficacy of long-acting agents or standard formulations using tid dosing for the treatment of pediatric ADHD, and 3) used both parent and teacher reports of the same measure of ADHD symptoms as a study outcome.
To examine the ability of parents to detect changes in their children’s ADHD symptoms relative to teachers’ reports of the same children, we compared the parent F test statistic to the teacher F test statistic for a given outcome measure. This F test statistic can be roughly interpreted as the magnitude of the drug-placebo difference for a given reporter. However, because the sample size and design can influence this statistic, we also calculated effect sizes for each parent and teacher report, because the effect size is standardized across sample sizes. We used the following formula to calculate the effect size eta2:
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1 and 2 are the numerator and denominator degrees of freedom for the F ratio. For each reporter, the effect size can be interpreted as a proportion of variance in the outcome rating accounted for by the drug-placebo manipulation. Thus, a comparison of parent effect sizes to teacher effect sizes can tell us to what extent parent reports detect change in children’s ADHD symptoms, compared with teacher reports. We then calculated a ratio of the effect sizes, where ratios larger than unity will indicate a more robust parent rating.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Our literature search identified 3 studies that matched our criteria: a randomized trial of MPH tid by the MTA Cooperative Group9; a randomized, double-blind study of extended-release ostomotic-release oral system (OROS) MPH by Wolraich et al10; and a randomized, double-blind study of extended-release mixed amphetamine salts by Biederman et al.11 The 3 studies are large scale and very well powered and are among the largest such trials ever conducted in pediatric psychopharmacology. Together, these studies included 1445 subjects. Two of the 3 studies were placebo-controlled, randomized clinical trials10,11; the third one9 randomly assigned subjects to 1 of 4 treatment approaches: medication management alone, behavioral treatment, combined treatment (behavioral management plus medication), and community treatment.
As shown in Table 1, these studies varied in length (from 3 weeks to 14 months) and in sample size (from 282 to 584 subjects). Two of the 3 studies used double-blinded assessments and were placebo controlled, whereas the third used community care as a control regimen. All studies had multiple levels of active treatment. Although there was no common outcome measure, all studies used either the Swanson, Nolan, and Pelham questionnaire (SNAP)12 and/or the Conners rating scales,13 both of which provide a comprehensive assessment of ADHD symptoms and associated behavior problems completed by parents and teachers.
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In the MTA study,9 children were assessed at baseline and at 3, 9, and 14 months. Statistical comparisons used all subjects’ assessments, estimating treatment-by-time effects. Assessments were done weekly for 4 weeks in the extended-release OROS MPH study,10 although primary analyses compared baseline assessments with week 4 assessments, with last observation carried forward. In the mixed amphetamine salts study,11 assessments were done every week for 3 weeks, but again the primary endpoint was the mean score at endpoint, compared across the 3 groups.
Across all 3 studies, teacher- and parent-reported measures documented significant improvement associated with psychopharmacologic treatment across all outcomes assessed (all P < .05). For assessing the magnitude of the response by reporter, ratios of F statistics were computed. As shown in Table 2, the ratio of F statistics were greater than unity in 2 of the 3 studies, indicating that the magnitude of the effect documented by parents’ reports were larger than the effect documented by teachers. The same pattern of results was found across the ratio of eta2 effect sizes, where the tid IR MPH and extended-release OROS MPH studies yielded effect size ratios that ranged from 1.1 to 4.8, indicating a larger effect captured by the parent report relative to the teacher report. In the mixed amphetamine salts study, the eta2 effect size ratios were <1.0, suggesting a larger effect measured by the teacher report.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a pooled analysis of the available literature to evaluate systematically the sensitivity of teachers’ and parents’ reports of therapeutic change in 3 large-scale clinical trials of youths with ADHD using long-acting treatments. Together, these 3 studies included 1445 children with ADHD. The results indicate that parent reports were as sensitive as teacher reports in detecting changes in pediatric ADHD symptoms in the clinical trials setting. Both sources of reports document statistically significant improvement in ADHD symptoms associated with pharmacologic treatment.
Moreover, in 2 of 3 studies evaluated, the magnitude of the significant effect was greater as measured by parent reports than by teacher reports. Although the parent reports of this study had a smaller effect size than that of teachers, they clearly showed robust separation from placebo, the same dose-response association, and the same sustained effect across the day as that observed in teachers’ reports, despite parents’ reports being ascertained on weekends.
The good convergence between parents’ and teachers’ reports identified in this study is consistent with previous findings on the subject. We know of only 1 other study that compared parent and teacher reports in a clinical trial setting. This was a meta-analysis comparing IR Adderall with placebo. In this study, Faraone and Biederman14 showed that teachers and parents both reported robust drug-placebo differences and that the 2 types of raters did not significantly differ from one another across 6 studies even when short-acting stimulants were used. In another meta-analysis of 62 randomized, placebo-controlled clinical trials of short-acting MPH in youths with ADHD,15 the effect sizes were 0.78 (95% confidence interval: 0.64–0.91) and 0.54 (95% confidence interval: 0.40–0.67) for teachers and parents, respectively. Although the teachers’ reports demonstrated a greater magnitude of effect, the parents’ reports still documented a significant effect, although their children were treated with short-acting MPH during school hours.
Clearly, the use of both parent and teacher reports for the diagnosis of ADHD as well as assessments of outcome in clinical trials of youths with ADHD enhances the certainty with which these assessments can be made.16,17 However, obtaining information from teachers, although highly desirable, is not always possible. Teachers are not available during school vacations, at a time when the family may choose to bring the child for evaluation. Also, in many educational systems, children will have multiple teachers in higher grades, making it difficult to obtain a meaningful "teacher’s report."
Furthermore, parent reports of ADHD can be used to assess the pervasiveness of symptoms. Although parents are not in the classroom with the child with ADHD, it is likely that they have heard a consistent pattern of complaints from teachers over the years because children who reach clinical centers are likely to have been symptomatic for several years before intervention takes place. Moreover, children with ADHD routinely engage in school-related activities at home during afternoons, evenings, and weekends through their homework and school-related projects. Finally, ADHD symptoms can manifest at home in activities unrelated to school, such as chores or play activities. Taken together, these results provide compelling support for the informativeness, reliability, and validity of parental reports for diagnostic and therapeutic considerations in the treatment of youths with ADHD.
The finding that parents consistently and robustly report outcome effects in clinical trials of youth with ADHD that are commensurate with teachers’ reports is not surprising considering that all 3 studies used a day-long approach to the treatment of the child with ADHD. The MTA study medicated children with tid IR MPH explicitly designed to cover the entire day. The 2 randomized clinical trials evaluated in this study tested extended-release formulations of MPH and amphetamines specifically designed to provide day-long coverage. All 3 studies also medicated the children 7 days a week. This approach to the treatment of the child with ADHD suggests that when children with ADHD are treated throughout the day and throughout the week, not only in the school setting and during school hours, the benefits of the treatment can be clearly observable by the parents.
The results reported in this analysis must be considered in light of some methodologic limitations. Despite the large number of participating subjects in each of the clinical trials available for pooled analysis, we were not able to perform a formal meta-analysis, because of the small number of studies (n = 3) and the lack of information required for meta-analytic techniques. Thus, P values could not be computed for a quantitative meta-analysis. Another limitation is the lack of consistency across studies in study design and outcome measures, yet despite these methodologic differences, the 3 studies yielded remarkably similar results, suggesting that the findings observed are robust.
Despite these considerations, our results indicate that parent reports can accurately and robustly inform outcome in clinical trials of children with ADHD when using long-acting treatments aimed at covering the entire day. These results challenge the heavy reliance on teachers’ reports in clinical trials of pediatric ADHD. Instead, they strongly suggest that the effects of a therapeutic agent can be documented successfully in the absence of teachers’ reports under double-blind conditions when testing a long-acting compound for ADHD. Although it is important to note that clinical treatment of individual patients may benefit from a teacher’s report, future clinical trials that rely on parental reports can be designed and implemented successfully, thereby greatly facilitating this research in pediatric ADHD populations.
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ACKNOWLEDGMENTS |
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This work was supported in part by US Public Health Service (National Institute of Mental Health) Grant R01MH-41314 (to Dr Biederman).
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FOOTNOTES |
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Received for publication Jun 14, 2002; Accepted Jul 7, 2003.
Reprint requests to (J.B.) Massachusetts General Hospital, Pediatric Psychopharmacology Unit (ACC 725), 15 Parkman St, Boston, MA 02114. E-mail: jbiederman{at}partners.org
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