Government initiatives in autism clinical trials

Randomized clinical trials remain the most valid method of testing the efficacy and safety of treatments. While efforts to elucidate the genetic and neurodevelopmental bases of autism are underway, clinicians and families are in need of scientifically valid information on how to best treat patients with autism. The effectiveness of many interventions currently used in communities has not been adequately tested. Given the high public health relevance of autism treatment research and the low interest of the pharmaceutical industry in autism, the role of the National Institutes of Health in supporting this research is paramount. Among recently launched initiatives in autism clinical trials, there are the Research Units on Pediatric Psychopharmacology Autism Network and the network of centers for Studies to Advance Autism Research and Treatment. These and other government activities in the area of autism clinical trials are here briefly reviewed.     

Evaluation of drug toxicity in clinical trials

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. A lecture on the subject of this paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005.     

Impact of recent findings on study design of future autism clinical trials

There are specific challenges to studying the design of pharmacologic trials in child/adolescent and adult autism, such as subject stratification and parallel versus crossover designs. This article describes how optimal study design is influenced by subject selection and outcome measures chosen. Lessons learned in study design from the Research Units on Pediatric Psychopharmacology Autism Network trial with risperidone, Seaver Center trials with fluoxetine and valproate, Dartmouth trials with amantadine, and National Institutes of Health secretin trials are highlighted. The Internet System for Assessing Autistic Children system for managing multicenter clinical trials in autism and statistical issues in autism research are also described.     

Incorporating multiple secondary targets into learning trials for individuals with autism spectrum disorder

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary target was presented in the consequence of each trial, and (d) no additional targets were presented trials. The participants acquired the majority of secondary targets. Presenting one or multiple secondary targets per trial, regardless of the location of these secondary targets, increased the efficiency of instruction in comparison to a condition with no secondary target.     

Assessing the remedy: the case for contracts in clinical trials

Current orthodoxy in research ethics assumes that subjects of clinical trials reserve rights to withdraw at any time and without giving any reason. This view sees the right to withdraw as a simple extension of the right to refuse to participate all together. In this paper, however, I suggest that subjects should assume some responsibilities for the internal validity of the trial at consent and that these responsibilities should be captured by contract. This would allow the researcher to impose a penalty on the subject if he were to withdraw without good reason and on a whim. This proposal still leaves open the possibility of withdrawing without penalty when it is in the subject's best interests to do so. Giving researchers recourse to legal remedy may now be necessary to protect the science, as existing methods used to increase retention are inadequate for one reason or another.     

Performance-based measures in autism: implications for diagnosis, early detection, and identification of cognitive profiles

Provides a critical review of performance-based assessment measures in autism. Currently, performance-based measures of autism are being explored in two domains: structured play sessions and cognitive-neuropsychological assessments. Structured play sessions are designed to elicit the behavioral symptoms associated with autism to provide a consistent and valid means of early detection and diagnosis of autism across different evaluators and settings. These structured play sessions provide a supplement to diagnostic instruments based on parental report. Cognitive-neuropsychological tasks have been used to identify possible underlying cognitive impairments in autism including executive function, theory of mind, selective attention, and abstraction. Currently, cognitive tasks are useful in treatment planning but are inappropriate for diagnostic purposes. Important goals for the future will be to integrate parent-report diagnostic interviews and structured play observations and to identify a profile of cognitive impairments that are specific to pervasive developmental disorders that can be incorporated into diagnostic protocols.     

Screening for autism in young children: The Modified Checklist for Autism in Toddlers (M-CHAT) and other measures

The literature on the importance of early identification and early intervention for children with developmental disabilities such as autism continues to grow. The increased prevalence of autistic spectrum disorders has fostered research efforts on the development and validation of autism-specific screening instruments for use with young children. There are currently several such autism-specific screening tools meant to be used with young children in various stages of development. Data from a few of these screening instruments have been published, and they include the Checklist for Autism in Toddlers (CHAT), Pervasive Developmental Disorders Screening Test (PDDST), Screening Tool for Autism in Two year olds (STAT), Checklist for Autism in Toddlers-23 (CHAT-23), and the Modified Checklist for Autism in Toddlers (M-CHAT). In this review, these five tools designed for use with children under three years old will be highlighted. In particular, the Modified Checklist for Autism in Toddlers (M-CHAT) will be discussed.     

Altruistic discourse in the informed consent process for childhood cancer clinical trials

Scholars have debated the role that altruistic considerations play--and should play--in recruitment and decision-making processes for clinical trials. Little empirical data are available to support their various perspectives. We analyzed 140 audiotaped pediatric informed consent sessions, of which 95 (68%) included at least one discussion of how participation in a cancer clinical trial might benefit: 1) the pursuit of scientific knowledge generally; 2) other children with cancer specifically; and 3) "the future" and other vaguely defined recipients. Clinicians initiated most (80%) of these discussions of altruism. The enrollment rate of children in the clinical trial was high (83%) overall, but not higher among children whose parents were involved in an altruism-oriented discussion. These findings suggest that: (1) clinicians invoke a spectrum of altruistic considerations rather than a single monothematic notion of altruism, and (2) the effect of altruistic considerations on subsequent enrollment decisions is marginal. While further research on this topic is warranted, bioethical debate should strive to reflect the diversity of altruistic discourse in clinical research encounters and to place this discourse in the context of other, including nonaltruistic, considerations.     

Placebo effect and randomized clinical trials

The achievement of optimal therapeutic results presupposes the use of appropriate treatment combined with maximal utilization of placebo effects. These aims may sometimes be difficult to satisfy in randomized clinical trials (RCTs). The question thus arises whether there is a conflict between the goals of therapy and those of experimental research; and if so, to what extent, and how is it handled in practice by clinicians and researchers. Various ethical problems have been discussed in several reports connected with RCTs. But we have found no discussion concerning the conflict between obtaining informed consent and promoting optimal placebo effects. Information about RCTs can be given in various ways. Sometimes appropriate information about RCTs to patients involves non-optimal utilization of placebo effects. This gives rise to ethical and methodological problems, which are discussed in this article.     

Pivotal areas in intervention for autism

Discusses several core pivotal areas that appear to be influential in intervention for autism. Literature and outcome data are reviewed with respect to several core areas that appear to be particularly helpful in intervention for autism, including improving motivation, responsivity to multiple cues, self-management, and self-initiation of social interactions. A conceptual framework is described, and outcome data are reviewed suggesting that when children with autism are motivated to initiate complex social interactions, it may reverse a cycle of impairment, resulting in exceptionally favorable intervention outcomes for many children. Because the peripheral features of autism can be numerous and extensive, the concept of intervention for pivotal areas of functioning may be critical if children are to be habilitated in a time- and cost-efficient manner.     

Toddler autism screening questionnaire: development and potential clinical validity

No feasible screening instrument is available for early detection of children with autism in Taiwan. The existing instruments may not be appropriate for use in Taiwan due to different health care systems and child-rearing cultures. The purpose of this study was to develop and test a screening questionnaire for generic autism. The initial 18-item screening questionnaire was developed by a child psychiatrist using face-to-face interviews with 10 families of children with autism and then tested on a sample of families of 18 children with autism and of 59 typically developing children. Of these 18 items, 15 had fair or better item discrimination (kappa >0.20) and were selected for the revised screening questionnaire. In the revised questionnaire, cutoff scores of 5 and 6 offered 100% sensitivity and 96.5% specificity, with the area under the receiver operating characteristic curve of 0.983. The revised screening instrument has high sensitivity and specificity, making it potentially useful for screening Taiwanese children at risk for autism. This instrument should be further tested in a population-based study.     

How clinical trials really work rethinking research ethics

Despite prevalent concerns about the ethical conduct of clinical trials, little is known about the day-to-day work of trials and the ethical challenges arising in them. This paper reports on a study designed to fill this gap and demonstrates a need to refine the oversight system for trials to reflect an understanding of this day-to-day work. It also illuminates ethical challenges that cannot be addressed by the oversight system and so necessitate a rethinking of the ethics of clinical trials.