SPECIAL SECTION: SPECIAL ARTICLES
How Can We Improve the Assessment of Safety in Child and Adolescent Psychopharmacology?

https://doi.org/10.1097/01.CHI.0000046840.90931.36Get rights and content

ABSTRACT

Objective

To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents.

Method

Strengths and limitations of current methodology were reviewed and possible alternatives examined.

Results

Research on the validity of safety evaluation has been extremely limited. No evidence-based “gold standard” exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered.

Conclusions

The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common “core,” to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.

Section snippets

What Do We Need to Know About the Safety of Psychotropic Medications in Children?

Safety is a relative concept. When defined as absolute absence of toxicity, safety cannot be experimentally “proven” in the same way as efficacy is demonstrated by rejecting a null hypothesis. However, it is possible to mount studies that are sensitive enough, because of experimental design, statistical power, and instrumentation, to detect clinically significant AEs associated with drug use. Failure by such studies to detect AEs, or detection of only minor AEs, would lead to the conclusion

Assessment of Drug Safety and Current Limitations

A variety of approaches and methods can contribute to the evaluation of drug safety in children, including both animal models and research in humans. The use of animal models to study the possible impact of medications on development is a promising area of investigation that remains in large part unexplored. Brain imaging techniques, such as proton magnetic resonance spectroscopy, have been applied to child psychopharmacology (Rosenberg et al., 2000) and may contribute to the assessment of drug

Analysis and Interpretation of Safety Data

Safety data present formidable challenges in analysis and interpretation (Lavori, 1986). These data sets are multivariate (many different types of AEs), sparse (only few items being endorsed), complex (involving severity and duration, with different possible patterns of occurrence), longitudinal (multiple assessments of the same subjects), censored (dropouts at different times), and incomplete (frequent missing data). Even if one limits an AE questionnaire to 10 items, their complete

Approaches to Improving Drug Safety Evaluation

Standardization of safety methodology is highly desirable, as it would facilitate meta-analyses and data interpretation, but it poses major challenges. Notwithstanding the issues already discussed, the fact remains that safety evaluation must contend with a host of different questions and situations. Type of drug being tested, stage of drug development, preexisting knowledge of safety profile, range of doses, and duration of treatment are all factors that influence the type of question to be

Conclusions

In reviewing the current methods used for evaluating drug safety in children, three major limitations emerge, each coupled, however, with a potential opportunity for improvement. The first is the considerable inconsistency in the way safety is assessed across pediatric psychopharmacological studies and settings. Although heterogeneity is justified by the variety of possible questions about “safety,” it should not prevent the adoption of standardized procedures (definitions, ascertainment,

REFERENCES (37)

  • J Biederman et al.

    Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder

    Pediatrics

    (1999)
  • T Brewer et al.

    Postmarketing surveillance and adverse drug reactions: current perspectives and future needs

    JAMA

    (1999)
  • EG Brown et al.

    The Medical Dictionary for Regulatory Activities (MedDRA)

    Drug Saf

    (1999)
  • GA Carlson et al.

    Stimulant treatment in young boys with symptoms suggesting childhood mania: a report from a longitudinal study

    J Child Adolesc Psychopharmacol

    (2000)
  • CR Culy et al.

    Lamotrigine: a review of its use in childhood epilepsy

    Paediatr Drugs

    (2000)
  • FE Dreifuss et al.

    Valproic acid hepatic fatalities: a retrospective review

    Neurology

    (1987)
  • JG Edwards et al.

    Prescription-event monitoring of 10,895 patients treated with alprazolam

    Br J Psychiatry

    (1991)
  • JR Farwell et al.

    Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence

    N Engl J Med

    (1990)

    • Cited by (49)

    • The preschool ADHD treatment study (PATS) as the culmination of twenty years of clinical trials in pediatric psychopharmacology

      2011, Journal of the American Academy of Child and Adolescent Psychiatry

    • Antipsychotics in children and adolescents: Increasing use, evidence for efficacy and safety concerns

      2009, European Neuropsychopharmacology

    • Psychopharmacology for children: From off label use to registration

      2009, European Neuropsychopharmacology

    • Meta-analysis of suicide-related behavior events in patients treated with atomoxetine

      2008, Journal of the American Academy of Child and Adolescent Psychiatry
      Citation Excerpt :

      Suicide-related scale items are potentially another way to assess the possible drug-related association, but because of the indication, many studies in the clinical development of atomoxetine for ADHD did not use depression rating scales that would allow such an analysis. Given the recent interest in suicidality in pediatric psychopharmacology studies, many comments have been made about the limitations of adverse event monitoring.34,59,60 Considering the limits of retrospective reviews of adverse events, suggestions for future studies include prospective monitoring of adverse events,58,59 wider use of data safety monitoring boards in early clinical drug development, pooling of clinical trial data in large independent research networks,61 and applying epidemiological methods to large health care databases.34,60

    • Texas children's medication algorithm project: Update from Texas consensus conference panel on medication treatment of childhood major depressive disorder

      2007, Journal of the American Academy of Child and Adolescent Psychiatry
      Citation Excerpt :

      In addition to the strategies for acute treatment, recommendations are provided for continuation and maintenance treatment. The consensus panel identified unique and important aspects of children and adolescents with MDD involving treatment and assessment issues (Vitiello et al., 2003). Therefore, stage 0 summarizes and emphasizes the following areas that need to be addressed before initiating medication treatment in children and adolescents with MDD.

    • Data safety monitoring boards and other study methodologies that address subject safety in "high-risk" therapeutic trials in youths

      2007, Journal of the American Academy of Child and Adolescent Psychiatry
    View all citing articles on Scopus

    Funding for this work was provided in part through contracts of the NIMH to Johns Hopkins University (N01MH60016; Principal Investigator: Mark A. Riddle, M.D.) and the Research Foundation for Mental Hygiene (N01MH60005; Principal Investigator: Laurence L. Greenhill, M.D.) for the Research Units on Pediatric Psychopharmacology research network.

    View full text
    Copyright © 2001 The American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.