Working Group Tasked with Studying Drug Development for Treating Autism

July 06, 2021

Researchers Focused on Advances, Challenges, Barriers, and Future Directions

Concerned with a lack of progress in pharmacological interventions for autism’s core deficits, the International Society for CNS Clinical Trials and Methodology (ISCTM) along with the European College of Neuropsychopharmacology (ECNP) created an autism spectrum disorder (ASD) working group to review and identify challenges encountered for developing drugs to treat the disorder. The working group, composed of experts from academia, clinical care, industry and regulatory agencies, was additionally charged with finding consensus on key issues including research tools and methodologies. The team also set out to generate recommendations for the field, funding agencies, potential sponsors and other autism community stakeholders. From the start of this initiative, the working group was challenged by the heterogeneous nature of ASD including the overall variability in severity levels, language skills, sociability, and intelligence. The working group quickly recognized that subtypes of autism exist and identifying these subtypes will be increasingly important for future research. Variability and subtypes in autism were identified as two of the major barriers for pharmacological development. Ultimately, the researchers realized that due to the lack of consistency in autism symptoms and a lack of understanding of the reasons for this variability, consensus on key issues was going to be nearly impossible. However, the team developed recommendations to enhance standardization, precision, and success of future ASD preclinical and clinical drug trials. These recommendations include:


  1. Move away from animal models purely based on behavioral phenotypes to more circuit-based approaches to improve translation
  2. Favor preclinical measures with direct translation to clinical endpoints
  3. Robust demonstration of compound engagement of target mechanism
  4. Convergence of effects across multiple preclinical models should be examined


  1. Replication of positive findings has high priority
  2. Prioritize additional treatment research on ASD co-occurring disorders
  3. Better basic characterization of study samples for cognitive ability, core symptom severity, gold standard diagnostic measures, language level, functional ability, and comorbidities
  4. Trials should include most commonly employed measures (e.g. SRS-2, ABC, RBS-R, CGI-I, Vineland), even as secondary endpoints, to facilitate combined/comparative analyses
  5. More outcome measures should be developed to target key domains/constructs such as RDoC systems (e.g. positive valence–social motivation)
  6. Preferred endpoints should have broader developmental and ability norms, and reliability/stability data
  7. Endpoints need demonstrated sensitivity to capture established clinically meaningful change, beyond their sensitivity to identify deficits or differences
  8. More outcome measures are needed with independence from confounding influence of cognitive or language ability
  9. Hypotheses should drive study design (including sample size, population stratification, etc.); trial length choice based on when changes are expected according to the hypothesis and the outcome measure
  10. Differential treatment impact according to cognitive ability needs broader investigation
  11. More research on utility of digital approaches with required data on feasibility, reliability, sensitivity to change, and convergent validity with standard behavioral measures
  12. Greater incorporation of perspectives of individuals with ASD and their families in the development of measures, nomination of meaningful endpoints, and trial design
  13. Pilot studies are still necessary for new compounds to test proof of mechanism/concept hypotheses, but are not sufficient for estimating effect size for repurposing compounds

In the end, the working group recognized that idiopathic ASD is the most complex of the neuropsychiatric and neurodevelopmental disorders. It is due to this fact that the team recognizes ASD drug development as extremely challenging. They believe that methodological advances will depend heavily upon research investments to refine clinical tools and identify new biologically based endpoints of key circuits involved in autism.

Original Study

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