The European Medicines Agency (EMA) on Friday released its first guidance to help drugmakers develop therapies to treat autism spectrum disorder (ASD).

The draft guideline seeks to provide advice on four critical areas of clinical development: diagnosis and inclusion criteria for patient selection in clinical trials, methods for assessing efficacy, clinical trial design and measuring drug safety.

Currently, ASD treatment focuses primarily on behavioral therapy and specialized education for patients. The disorder primarily affects boys and is estimated to occur in about one percent of the world population. A recent analysis by the US Centers for Disease Control and Prevention found that one in 68 children in the US have autism. While rates of autism diagnosis have steadily increased in recent years, experts disagree whether this is due to improved screening and diagnosis or if the condition is becoming more common.

To date, no drugs have been approved to treat the core symptoms of ASD: impaired social interaction, abnormal communication and restricted and repetitive behaviors and interests.

While the US Food and Drug Administration (FDA) has approved two drugs, Risperdal and Abilify, to treat irritability in children with ASD, EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended against an autism indication for both drugs.

Other types of drugs, including certain antidepressants, antipsychotics, attention deficit hyperactivity disorder (ADHD) treatments and the drug naltrexone, which is used to treat drug and alcohol dependence, are used off-label to treat ASD symptoms.

According to EMA, research is currently underway into new potential treatments to treat ASD, including molecules affecting glutamate, gamma-aminobutyric acid (GABA) and the serotonergic system, as well as to identify potential biomarkers relevant to the disorder.

Draft Guideline

First, EMA says that any sponsors seeking an autism indication for a drug must demonstrate efficacy on one or more of the disorder's core symptoms, and should show both short- and long-term efficacy.

The agency also discourages sponsors from seeking "single symptom" indications, unless a sponsor can show that the effect is "specific to autism and would not be applicable in more general populations."

Patient Selection

Importantly, EMA says, sponsors must ensure their clinical development program includes patients covering the full array of age and severity, and should include "a sufficient number of patients from the EU." Because ASD presents differently in adults and children, EMA says sponsors should conduct separate trials to demonstrate efficacy in adults and children, and should not extrapolate effects from one age group to another.

Also, because ASD is a lifelong condition, EMA recommends that sponsors include enough elderly patients in a trial to determine the benefit/risk for the elderly.

In terms of inclusion from trials, EMA says patients should be diagnosed by the latest available Diagnostic and Statistical Manual of Mental Disorders (DSM). Additionally, the agency says sponsors may use a biomarker to screen trial participants, if one becomes well-validated for ASD.

The agency also lists four potential exclusion criteria that sponsors should consider:

• Severe co-morbid conditions that may interact with study procedures
• Newly initiated or recently changed pharmacotherapy
• Newly initiated or recently changed formal behavioral, cognitive or cognitive-behavioral therapy

Safety and Efficacy Considerations

To measure the efficacy of a treatment during a trial, EMA says sponsors should rely on self-reported outcomes by patients, as well as their parents and teachers.

EMA also encourages sponsors to use symptomatic, functional and global scales to measure the effect of a treatment. However, the agency notes that there are no recognized functional scales for ASD but sponsors are encouraged to develop one.

Additionally, EMA suggests that sponsors consider pre-specifying one or more secondary outcomes their study will measure, such as sleep disturbance.

While EMA says that adverse events should be monitored based on treatment duration, age and other "relevant variables," the agency says that special attention should be paid to adverse events effecting the central nervous system, endocrine system and events leading to rebound, withdrawal or dependence.

Again, because ASD is a lifelong disorder and is present during childhood, EMA says that sponsors must include evidence of long-term safety and focus heavily on "effects on the developing brain and body."

EMA Press Release, Draft Guidance