Representativeness of Participants in a Clinical Trial for Attention-Deficit/Hyperactivity Disorder? Comparison With Adults From a Large Observational Study
Background: Clinical trials have demonstrated that pharmacotherapies can safely treat attention-deficit/hyperactivity disorder (ADHD) in adulthood. Eligibility criteria in these trials may significantly limit their external validity by excluding a significant portion of adults with ADHD in the general population. In particular, exclusion criteria may frequently exclude individuals with comorbid mental health conditions, which are common in the adult ADHD population.
Method: We addressed the representativeness of clinical trials by comparing 146 adult clinical trial participants with DSM-IV ADHD and a community sample composed of 124 adults with DSM-IV ADHD and 123 non-ADHD controls. Subjects were compared on socioeconomic status, Hollingshead occupational code, cognitive measures, lifetime psychopathology, and Global Assessment of Functioning (GAF) scale ratings.
Results: Adults with ADHD in the community sample had higher rates of lifetime psychiatric comorbidity, lower GAF scores, and lower occupational codes than those in the clinical trial. The clinical trial eligibility criteria would have excluded 61% of community sample adults with ADHD. This excluded portion of the community sample had higher rates of lifetime psychiatric comorbidity and lower GAF scores than clinical trial participants.
Conclusions: Adults with ADHD participating in the clinical trial had less evidence of functional impairment and endorsed less psychiatric comorbidity than the majority of community sample subjects with ADHD. This suggests that findings from clinical trials may have limited external validity for adults with ADHD in the general population, particularly for those adults with ADHD with the greatest burden of comorbid psychopathology.
J Clin Psychiatry 2010;71(12):1612-1616
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: May 08, 2009; accepted July 14, 2009.
Online ahead of print: August 10, 2010 (doi:10.4088/JCP.09m05344pur).
Corresponding author: Craig B. H. Surman, MD, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Ste 2000, 185 Alewife Brook Pkwy, Cambridge, MA 02138 (email@example.com).
In recent years, several clinical trials for adults with attention-deficit/hyperactivity disorder (ADHD) have contributed to the advancement of safe and effective treatment for this disorder. However, because clinical trials have inclusion and exclusion criteria, it is possible that subjects participating in these clinical trials are not representative of the larger population of adults with ADHD in the community. Of particular concern is the routine exclusion of subjects with comorbid psychiatric disorders from clinical trials of treatments for ADHD in adults, which are common in adults with ADHD in the general population.
Whether adults with ADHD participating in clinical trials are representative of the greater population of individuals with the disorder has implications for the external validity of these studies. If subjects with ADHD participating in clinical trials differ from subjects with ADHD in the general population, evidence from clinical trials may not provide accurate guidance for practitioners treating adults with ADHD that would have been excluded from clinical trials.
The main aim of the present study was to investigate whether adults with ADHD participating in clinical trials are representative of adults with ADHD in the community. To this end, we systematically identified and compared clinical correlates of adults with ADHD participating in a clinical trial and subjects with ADHD identified in a large community observational study. We hypothesized that subjects ascertained from the community will manifest higher levels of psychosocial impairments and psychiatric comorbidity than those participating in a clinical trial.
The clinical trial participants consisted of 146 adults with ADHD between 19 and 60 years of age recruited for participation in a double-blind, randomized, placebo-controlled, 6-week trial of methylphenidate treatment ascertained from clinical referrals and advertisements in the greater Boston area.1 Subjects had to satisfy full diagnostic criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD on the basis of clinical assessment and confirmed by structured diagnostic interview.2 We excluded potential subjects if they had clinically significant chronic medical conditions; abnormal baseline laboratory values; an Intelligence Quotient (IQ) score less than 80; delirium, dementia, or amnestic disorders; a current impairing psychiatric condition other than ADHD (eg, current major depression, panic disorder, or generalized anxiety disorder); history of a clinically unstable psychiatric condition (eg, history of bipolar disorder or psychosis, suicidality); drug or alcohol abuse or dependence within the 6 months preceding the study; or a previous adequate trial of stimulant treatment (> 0.5 mg/kg/d of methylphenidate or equivalent). Current use of psychotropics, other than stable treatment with selective serotonin reuptake inhibitors, was also exclusionary. We also excluded pregnant or nursing women from participation.
The community sample consisted of 124 subjects ascertained as part of a naturalistic study of ADHD in adults between the ages of 18 and 55 years.3 These subjects were ascertained from referrals to the Massachusetts General Hospital and advertisements in the greater Boston area. All subjects met full DSM-IV criteria for ADHD on the structured diagnostic interview,2 with onset of symptoms by age 7 years. Subjects were excluded if they had major sensorimotor handicaps (eg, deafness, blindness) or psychosis. Non-ADHD controls were recruited through advertisements in the greater Boston area.
Both studies excluded subjects with an inadequate command of the English language or an IQ score less than 80, as measured by an IQ estimate from the Block Design and Vocabulary subtests of the Wechsler Adult Intelligence Scale-Revised.4 No ethnic or racial group was excluded in these studies. These studies were approved by the institutional review board, and all subjects completed a written informed consent process before inclusion in the study.
Subjects in both studies were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders5 supplemented with modules from the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version6 to assess ADHD and other childhood disorders. We conducted direct interviews with subjects. We considered a disorder positive if DSM-IV diagnostic criteria were unequivocally met. Although standardized algorithms were used to determine each diagnosis, interviewers conducting the assessment needed a mechanism to determine the clinical relevance of symptoms when subjects were only able to provide unclear or imprecise information. Thus, a committee of board-certified child and adult psychiatrists, who were blind to the subject’s ADHD status, referral source, and all other data, resolved diagnostic uncertainties. Diagnoses presented for review were considered positive only when the committee determined that diagnostic criteria were met to a clinically meaningful degree. We estimated the reliability of the diagnostic review process by computing Îº coefficients of agreement for clinician reviewers. For these diagnoses, the median reliability between individual clinician- and the review committee-assigned diagnoses was 0.87. The Îº coefficients for individual diagnoses included the following: ADHD (1.0), conduct disorder (1.0), major depression (1.0), bipolar disorder (0.78), separation anxiety (0.89), agoraphobia (0.80), panic disorder (0.77), substance use disorder (1.0), and tics/Tourette’s disorder (0.68).
The interviewers were blind to the subject’s ascertainment group and all prior assessments. The interviewers had undergraduate degrees in psychology and were extensively trained. First, they underwent several weeks of classroom-style training, learning interview mechanics, diagnostic criteria, and coding algorithms. Then, they observed interviews by experienced raters and clinicians. They subsequently conducted at least 6 practice (nonstudy) interviews and at least 3 study interviews while being observed by senior interviewers. Trainees were not permitted to conduct interviews independently until they executed at least 3 interviews that achieved perfect diagnostic agreement with an observing senior interviewer. J.B. supervised the interviewers throughout the study. We computed Îº coefficients of agreement by having experienced, board-certified child and adult psychiatrists and licensed clinical psychologists diagnose subjects from audiotaped interviews. Based on 500 assessments from interviews of children and adults, the median Îº coefficient was 0.98. The Îº coefficients for individual diagnoses included the following: ADHD (0.88), conduct disorder (1.0), major depression (1.0), mania (0.95), separation anxiety (1.0), agoraphobia (1.0), panic disorder (0.95), substance use disorder (1.0), and tics/Tourette’s disorder (0.89).
Interviewers assessed the degree of impairment on daily functioning associated with each disorder that subjects endorsed on a 3-level ordinal scale: minimal (ie, little to no impairment), moderate (ie, difficulties in daily life tasks), or severe (ie, unable to perform essential daily tasks). We analyzed major depression only if the depressive episode was associated with severe impairment, in order to avoid false-positive diagnoses. This is consistent with prior research methods.7,8
Socioeconomic status (SES) was measured by the Hollingshead measures, in which occupational and educational statuses are coded between 1 and 7, with higher numbers reflecting lower social status, and these items are weighted to produce a total SES score, with low values indicating high SES.9 As a measure of overall functioning, we used current and past lowest Global Assessment of Functioning (GAF) scale scores.
Comparisons were made between subjects with ADHD from the clinical trial (clinical trial ADHD sample, n = 146), subjects with ADHD from the naturalistic study (community sample ADHD, n = 124), and non-ADHD controls from the naturalistic study (community sample non-ADHD, n = 123). Age and sex were compared between the groups to allow significant differences to be controlled for in all subsequent analyses. Comparisons were also made between the clinical trial ADHD group, subjects with ADHD from the naturalistic study who would have met inclusion criteria for the clinical trial (screened in, n = 48), and subjects with ADHD from the naturalistic study who would have been excluded from the clinical trial (screened out, n = 76). Linear regression was used to analyze continuous variables (eg, full-scale IQ), logistic regression was used for binary variables (eg, individual diagnoses), negative binomial regression was used for count variables (eg, number of comorbidities), and ordered logistic regression was used for ordinal variables (eg, SES).
We also compared clinical trial subjects with community sample subjects who were likely to have met the inclusion and exclusion criteria for the clinical trial. We categorized individuals from the community sample as "screened out" if they met criteria for current subthreshold or full psychosis, severely impairing major depression, generalized anxiety, panic disorder, agoraphobia, anorexia, bulimia, alcohol or drug abuse or dependence, or bipolar disorder. Individuals were also excluded if they met criteria for any alcohol or drug abuse or dependence in the past 2 years.
Sociodemographic Characteristics of the Sample
Clinical trial subjects and community sample ADHD subjects were both significantly more likely to be older than the community sample non-ADHD group (Tables 1 and 2). Thus, all subsequent analyses controlled for these variables.