Autism spectrum disorder clinical trials: One step at a time

The National Institute of Mental Health (NIMH) recently announced a new approach to funding clinical trials, reasoning that a new way of doing business was needed because treatment research had stalled (Insel, 2014). Funding of trials will follow an “experimental medicine approach,” where the intervention serves as a potential treatment and as a probe to generate information about the mechanisms underlying a disorder. A positive trial requires ameliorated symptoms and a demonstrable effect on a target, such as a neural pathway implicated in the disorder. This approach favors smaller samples; the goal is to quickly determine whether it is worth pursuing further testing. The hope is that more targeted trials will generate information on the mechanisms underlying a disorder, accelerate the pace of new drug discovery, and save time and money. This approach is well accepted for drug development, but also has implications for psychosocial treatments. This new approach made me reflect on the state of autism spectrum disorder (ASD) treatment research. As an exercise, I reviewed the content of three journals with the highest impact factors among journals focusing exclusively on ASD research: Autism Research, Journal of Autism and Developmental Disorders, and Autism: International Journal of Research and Practice. According to the ISI Web of Knowledge, the 5-year impact factor for all three journals was above 3.8, and they were in the top 10 Developmental Psychology journals in 2014. From 2010 to 2015, they published a total of 171 treatment studies. To put things into perspective, 2,358 papers were published in these three journals over that 6-year period. This means that about 7% of articles were devoted to treatment studies. This 7% sounds less impressive than 171 studies, an absolute number that is far larger than what was published in a 6-year span 25 years ago. Of course, many treatment studies are published in other high-profile journals because of their potential impact. Why relatively so few treatment studies? Because they are labor-intensive and expensive. Study teams (e.g. therapists, physicians, blind evaluators, research coordinators, parents, and children) take part in repeated visits and assessments. Randomized controlled trials (RCTs) do not mesh well with academic environments that reward speed and quantity. Involved treatment studies are not the untenured scholar’s friend. For instance, both our recent parent training trial (Bearss et al., 2015) and atomoxetine and parent training study (Handen et al., 2015) took about 6 years to execute. This number approaches 10 years when including grant and manuscript writing. Perhaps an experimental medicine approach will spark more treatment research by encouraging smaller samples, thus shortening the time to publication. Perhaps it will lead to more head-to-head comparisons and reduce comparisons with treatment as usual (TAU) or waitlist control (WLC) groups, seen too often in the psychosocial literature. In recent reviews of social skills treatment studies (Kaat and Lecavalier, 2014) and parent training studies (Nevill et al., in preparation), we found that 27 out of 37 (73%) RCTs adopted TAU or WLC conditions. As noted below, this state of affairs is suboptimal. The good news is that 27 of these 37 studies (73%) were published after 2010. Thus, there have been more RCTs on these topics in the past 6 years than ever before. One reason TAU and WLC groups are used is that they are inexpensive. The “flip side” of lower cost is a real threat to the internal validity of the experiment. After all, randomization and control conditions are the principal methods of ensuring that the outcome for a trial is attributed to the treatment and not to any alternative explanation such as therapist attention, expectations of improvement, or biasing cognitive dissonance of informants (“If I put this much effort into coming for treatment, it must be useful”). Control conditions can have a very substantial impact on conclusions of the clinical trial; the effect of an intervention is calculated as the difference between the effect in the treatment group and the effect in the control group. If the control condition is not credible, it will erroneously magnify the difference between groups. The effects of differential attention and expectations of improvement can be considerable. Consider the following two examples. A total of 34% of participants in the placebo group in King et al.’s (2009) citalopram study had Clinical Global Impressions–Improvement (CGI-I) scores of Much Improved or Very Much Improved at the end of their 12-week trial targeting repetitive behaviors, the same as for children taking active medication (33%). Similarly, 40% of the parents in the attentional-control group of our parent training study to reduce behavior problems were considered positive clinical responders on the CGI-I at the end of the 24-week trial, compared to 69% in the experimental group (Bearss et al., 2015). Had a WLC condition Autism spectrum disorder clinical trials: One step at a time 623111 AUT0010.1177/1362361315623111AutismLecavalier research-article2015