Improving Fragile X and Autism Related Clinical Trials.

Walter KaufmannDr. Walter Kaufmann, the co-director of the Fragile X Syndrome Program at Boston Children’s Hospital has written a terrific article, “Autism clinical trials are ripe for improvement.”

He references the arbaclofen trials conducted by Seaside Therapeutics and the disappointment over the termination of the open-label fragile X trials. He raises three key issues with how current trials are conducted. To get a better picture of how clinical trials usually get performed, visit

“First, the cohort analysis approach to drug trials may not be the most appropriate for conditions that are highly heterogeneous in their causes and symptoms. One can argue that, from the outset, only a subgroup of individuals would be expected to respond to the drug. However, that raises the question of how to distinguish the group of potential responders. Behavioral rating scales, such as those used in the arbaclofen trials, have important limitations in defining autism. For instance, social avoidance seems to better describe social anxiety than the aloofness that characterizes ASD. Moreover, there is an important element of subjectivity in behavioral evaluations, as illustrated by the need to maintain the same observer throughout the trial.

Observational research commonly employs two analytical approaches: the use of multiple complementary measures (“converging evidence”) and biomarkers (objective, instrument-based measures). These approaches are not applied to drug trials since they are not part of the FDA regulatory process. Thus, the positive Phase 2 trials of arbaclofen—while unique in the magnitude and specificity of social improvement—were considered failures, because only secondary measures or post-hoc analyses demonstrated efficacy.

Finally, we need to redefine endpoints. If the novel treatments for ASD target mechanisms of disease and not symptoms, why should we continue focusing on improving a specific symptom? For some patients with fragile X, a drug may be efficacious for ASD symptoms; for others, it may reduce attention deficits or other behavioral problems. A more personalized approach to measuring outcomes, using biomarkers, has been proposed for other disorders, such as traumatic brain injury.”

Dr. Kaufmann concludes with this:

“Until all these issues are addressed, it will be difficult to conclude whether or not a drug trial was successful. Under the current approach, there is a potential for missing valuable new treatments—a huge loss for individuals and families with ASD and related disorders.”

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