EMA updates guideline on developing drugs for bipolar disorder

The European Medicines Agency (EMA) on 9 September proposes updating its guideline on developing drugs for treating bipolar disorder (BD) to reflect new medical understanding of the disease.
 
The guidance would replace the current 23-year-old version issued in 2001. EMA said it made several changes to reflect information in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). EMA originally announced plans to update the guidance in a  2016 concept paper. (RELATED: European Regulatory Roundup, Regulatory Focus 4 August 2016).
 
With this update in the DSM-5, BD and related disorders have been separated from depressive disorders, and bipolar disorder II (BD II) is no longer considered a milder form of bipolar disorder I (BD I). Also, a criterion for manic and hypomanic episodes has been changed to stress changes in activity and energy.
 
According to EMA, approximately 40 million people globally have BD, and the risk of suicide is 10‐30 times greater for individuals affected by this disorder relative to the general population. The guidance states that while the etiology and pathophysiology of BD are unknown, genetic research using Genome Wide Association Studies (GWAS) and Copy Number Variations (CNV) methodologies has provided some insight on the disease’s neurobiology.
 
The guidance notes that while there are several behavioral, genetic and neuroimaging biomarkers for identifying at risk patients, the data is still too heterogeneous and not suitable for “fingerprinting.”  
 
The guidance addresses clinical pharmacology studies; assessing therapeutic efficacy; addressing specific claims such as treatment resistance and improvement in cognitive functions; use of this drug in special populations such as older people and children; and safety evaluation.
 
For clinical pharmacology studies, the guidance notes that the use of receptor occupancy positron emission tomography (PET) studies to detect structural or functional changes in the brain that may be useful in dose finding studies.
 
For assessing clinical efficacy, the guidance recommends that sponsors assess the treatment on manic or depressive symptoms in the acute phase and in the maintenance treatment period. The guidance notes that, “even if a product is only effective in one situation e.g. in the treatment of acute manic episode instead of the entire spectrum of the disorder, including depressive episodes, it is important to know whether it provokes the opposite pole of bipolar disorder (e.g. induces a switch from mania to depression).”
 
Patients in these studies should be diagnosed and classified according to DSM-5 or International Classification of Diseases (ICD) 11 criteria. The diagnosis should be made by a qualified psychiatrist and confirmed with the use of a structured assessment tool such as the Structured Clinical Interview for DSM-5 Axis I Disorders (SCID-I).
 
The guidance recommends the use of double-blind, randomized, parallel group, placebo-controlled studies. EMA notes that crossover designs “are unsuitable for studies in patients with BD.”
 
A three-week clinical study is the recommended duration for demonstrating efficacy in acute mania while in mania, a 50% improvement of a patient on a usual rating scale is accepted as a “clinically relevant response.”
 
The guidance does not recommend studies in children under the age of 13 years as “there is insufficient evidence for the existence of BD” in this population.
 
EMA is accepting comments on the guidelines until 31 March 2025.
 
Draft guideline