PEDIATRICS Vol. 114 No. 4 October 2004, pp. 1132-1133 (doi:10.1542/10.1542/peds.2004-1591)
Flawed Attention-Deficit/Hyperactivity Disorder Medication Comparison: In Reply
James M. Swanson, PhD (on behalf of the COMACS Group)Department of Pediatrics
University of California
Irvine, CA 92612
Dr Adesman1 suggests that our study2 was "unfair and mostly irrelevant from a clinical perspective" because we compared formulations of methylphenidate, Metadate CD (MCD) and Concerta (CON), that "are not substitutes for each other." This is an unwarranted criticism of our design. We used a nonequivalence design and large sample size to test a null hypothesis about expected small differences generated from known pharmacokinetic and pharmacodynamic properties of CON3 and MCD.4 Evaluation of "substitutes" would require a noninferiority rather than nonequivalence design and acceptance not rejection of the null hypothesis.
Dr Adesman implies that our choice of doses was a planned methodologic flaw related to the source of support and alludes to differences in the immediate-release (IR) components of CON and MCD to support his contention. However, in our article, we clearly stated that "MCD releases 50% more IR MPH ... than CON"2(p.e208) for near-equal daily doses, and we used this5 to formulate our null hypothesis of no difference, which we were able to reject.
Dr Adesman objects to our primary hypothesis about effects during the school day, but we also evaluated a later time point and reported at the 12-hour assessment that "CON was statistically significantly better than MCD and PLA [placebo]"2(p.e210) (see figure 1 in ref 2). A biased study would have included only time points when superiority of MCD was expected and not an assessment time when superiority of CON was expected. We also performed secondary analyses of morning effects, which showed that for "the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs [effect sizes] were large and indistinguishable."2(p.e207)
For the doses evaluated, our study showed no overall superiority for either product but instead documented a changing pattern of superiority throughout the 12-hour study day and explained it in terms of known pharmacokinetic/pharmacodynamic relationships. We believe that this result demonstrates scientific rigor (not bias) and is highly relevant (not irrelevant) because it provides an empirical basis for practical choices among alternative options for clinical treatment.
Food may6 or may not7 affect the pharmacokinetic properties of methylphenidate, but few studies8 have evaluated food effects on efficacy. It was not feasible to double the size of an already large study to address this factor, but in our methods section we should have stated that food intake was controlled by administering the morning dose after an overnight fast and providing a standardized breakfast 
1 hour later.
REFERENCES
- Adesman A. Flawed attention-deficit/hyperactivity disorder medication comparison [letter].
Pediatrics. 2004;114
:1132
[Free Full Text] - Swanson JM, Wigal SB, Wigal T, et al. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the COMACS Study). Pediatrics. 2004;113(3) . Available at: www.pediatrics.org/cgi/content/full/113/3/e206
- Swanson J, Gupta S, Lam A, et al. Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.
Arch Gen Psychiatry. 2003;60
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–211
[Abstract/Free Full Text] - Wigal SB, Sanchez DY, DeCory HH, D'Imperio JM, Swanson JM. Selection of the optimal dose ratio for a controlled-delivery formulation of methylphenidate. J Appl Res. 2003;3 :46 –63
- Swanson J, Lerner M, Wigal T, et al. The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications. J Atten Disord. 2002;6(suppl 1) :S73 –S88
- Chan YP, Swanson JM, Soldin SS, Thiessen JJ, MacLeod SM, Logan W. Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid.
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[Abstract/Free Full Text] - Gonzales MA, Pentikis HS, Andrl N, et al. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther. 2002;40 :175 –184[Web of Science][Medline]
- Swanson JM, Sandman CA, Deutsch C, Baren M. Methylphenidate hydrochloride given with or before breakfast: I. Behavioral, cognitive, and electrophysiologic effects.
Pediatrics. 1983;72
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[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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- Flawed Attention-Deficit/Hyperactivity Disorder Medication Comparison
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  J. M. Swanson Flawed Attention-Deficit/Hyperactivity Disorder Medication Comparison: In Reply Pediatrics, October 1, 2004; 114(4): 1132 - 1133. [Full Text] [PDF]
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