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The recent news regarding Le Noury and colleagues’re-analysisof a 14-year old study demonstrating the safety of paroxetine (Paxil) in children and teenagers (2015; British Medical Journal), has driven international attention to how drug manufacturers evaluate and document the safety and efficacy of new drugs. To sum up, the authors concluded that the secondaryanalysis of existing data from Study 329 (Keller et al., 2001) demonstrated clinically significant increases in harms, including suicidal ideation and behavior (SIB) and other serious adverse events in individuals taking paroxetine, contrasting with the results of the original study, and how conclusions were reported in the original publication.
Although there are questions on suicidal ideation within validated depression measures (e.g., K-SADS-L; HAM-D), the original Keller et al., 2001 paper did not use a formal assessment tool to identify and mitigate risk of SIB. The new findings of Le Noury and colleagues (2015) provide evidence for a utilizing a standardized, anchored approach to categorizing suicidality, which can provide an accurate and comprehensive identification of suicidal events during and after participation in a clinical trial.
FDA’s Guidance re: Suicidality Assessment in Drug Development and Clinical Trials
It is coincidental that the questions surrounding paroxetine are occurring this month, as September marks the 5 year anniversary of the U.S. FDA’s Guidance to Industry, “Suicidality: Prospective Assessment of Occurrence in Clinical Trials.”First released in September 2010, the FDA’s draft guidance cited the Agency’s current thinking on the assessment of treatment-emergent suicidality. Revisions issued in August 2012reinforcedits applicationand principles, and brought more clarity to the expectations of when, where and how to assess SIB.
FDA suggests that, “…prospective suicidal ideation and behavior assessments should be carried out in all clinical trials involving any drug being developed for any psychiatric indication, as well as for all antiepileptic drugs and other neurologic drugs with central nervous system (CNS) activity, both inpatient and outpatient, including multiple-dose phase 1 trials involving healthy volunteers1.”
The FDA’s revised Guidance recommends the specific activities that researchers should include when conducting clinical trials with products that have high-potential SIB risk, and includes expectations of what types of data are to be delivered to evaluate SIB.
Overcoming the Challenges of Suicide Risk Assessments
Procedural variances in the way SIB risk and all clinical assessments are performed by human raters are associated with a number of shortcomings negatively impacting the reliability of results. Even with extensive training, rater skills deteriorate over time and clinicians are often influenced by prior experiences with patients, recency errors (rater’s tendency to allow more recent incidents (either effective or ineffective) of patient behavior to carry too much weight in evaluation of behavior over an entire rating period) or halo effect errors (rater’s overall positive or negative impression of a patient leads to rating him/her the same across all rating dimensions). Further, performing these risk assessments in a traditional manner – on paper and rated by the clinician – represents a significant burden for the investigative site, requiring additional staff training to ensure proper SIB evaluation. As a result, researchers are actively looking for ways to overcome these limitations.
Accurate assessment of potential SIB among patients participating in clinical trials is very important so that appropriate measures can be taken to prevent a future completed suicide.The eC-SSRS, a self-rated electronic version of the scientifically proven Columbia Suicide Severity Rating Scale (C-SSRS) has been cited by the FDA as a way of meeting this assessment requirement. It is administered via AVERT™, ERT’s electronic suicide risk assessment system that efficiently and effectively captures critical SIB data via audio (phone) or visual (web/tablet) interfaces. AVERT facilitates the collection of high quality, unbiased data directly from the patient. And, since self-report enables increased patient candor, patients are more likely to reveal higher frequency and severity of SIB than in interview-ascertained models, resulting in higher quality data.
Through more reliable data, suicidal ideation and behavior assessment tools are increasingly being used to overcome the shortcomings associated with traditional, paper/clinician-based assessments. AVERT provides sponsors with a fast and reliable means of collecting valuable information relating to the welfare and safety of patients and ultimately allowing swift and effective interventions for at risk subjects.
Protecting Patients and Compounds
Now more than ever, the pharmaceutical industry needs to take a closer look at their drug development pipelines to confirm they are taking appropriate, effective steps to ensure patient safety by identifying the risk of treatment-emergent SIB during clinical trials. Drug developers should consider using proactive and efficient approaches to incorporate SIB assessment into clinical trials consistent with the assessment of vital signs. Additionally, for drugs with a long half-life, assessment of SIB in patients should be maintained even after the clinical trial has ended. By doing so, drugdevelopers can ensure patient safety, efficiently adhere to the requirements of the FDA Guidance, and recognize additional benefits, including the likelihood of protecting their compounds from false positive findings.
For more information, join us for a complimentary webinar on November 5, 2015 ERT scientists will present a complimentary webinar, “Assessing Suicide Risk in Clinical Development.” Register here!
1) Guidance for Industry Suicidal Ideation andBehavior: ProspectiveAssessment of Occurrence inClinical Trials. FDA. August 2012
2) Gao K, Wu R, Wang Z, Ren M, Kemp DE, Chan PK, Conroy CM, Serrano MB, GanocySJ, Calabrese JR. Disagreement between self-reported and clinician-ascertained suicidal ideation and its correlation with depression and anxiety severity in patients with major depressive disorder or bipolar disorder. J Psychiatr Res. 2015 Jan;60:117-24. doi: 10.1016/j.jpsychires.2014.09.011.