Suicide risk assessment in clinical trial drug development: part 2
Kelly Posner, Ph.D. – Professor of Psychiatry at Columbia University
John Greist, MD – Professor Emeritus of Psychiatry at the University of Wisconsin School of Medicine and Public Health and CEO at Healthcare Technology Systems, Inc.
James Mundt, Ph.D. – Consultant
As discussed in Suicide Risk Assessment in Drug Development: Part 1, in 2012, the Food and Drug Administration (FDA) issued guidance to the pharmaceutical industry following spontaneous reports of suicides associated with an approved smoking cessation drug. The ensuing “black box” label warning had negative consequences for both the manufacturer and patients, and remained in place for seven years while an expensive and time-consuming post-marketing randomized clinical trial was conducted to resolve the FDA’s safety concerns. This second blog discusses Clinical Outcome Assessments (COAs) to accurately evaluate suicidal ideation and behavior (SIB) in clinical trials.
The 2012 FDA guidance, Guidance for Industry Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials, identifies the Columbia-Suicide Severity Rating Scale (C-SRSS) for obtaining the best prospective data on suicide risk during drug development. Specifically, it states:1
“…the C-SSRS is a prospective assessment instrument…and this instrument would be acceptable for the purpose of these studies. The C-SSRS involves a series of probing questions to inquire about possible suicidal thinking and behavior, and this process is conducted at baseline (this would be a lifetime suicidal ideation and behavior assessment) and at each patient visit…”
Rationale for Patient-Reported eC-SSRS
The clinician-administered C-SSRS is the gold standard for suicide risk assessment. Developed by Dr. Posner and her colleagues at Columbia and other Universities, the C-SSRS was refined over a decade by suicidology experts at Columbia and other major research centers. An alternative/adjunctive approach for assessing SIB, the electronic patient-reported version of C-SSRS (eC-SSRS) was developed and validated by ePRO experts working with Dr. Posner. These self-reported assessments provide more honest and candid responses and clearer signals for assessing the effects of medications on suicide risk.2
“eC-SSRS eliminates rater bias and increases disclosure of suicidal ideation and behavior in all comparisons with face-to-face assessment in adults and adolescents.”3
John Greist, MD – Professor Emeritus of Psychiatry, CEO at Healthcare Technology Systems
Patient-reported eC-SSRS assessments take little time to complete. Data from almost 15,000 administrations of the eC-SSRS found an average completion time of 3.5 minutes for patients without positive findings and 7 to 8 minutes for patients with positive results.4 To date, more than 700,000 drug development assessments across psychiatric and non-psychiatric programs have used patient-reported eC-SSRS.
The Role of Patient-Report Data in Assessing Suicide Risk
Prior to the issuance of the 2012 FDA guidance, a 2009 study conducted by Kobak, et al. identified sources of unreliability in clinician-reported depression ratings. Importantly, differences between clinicians were responsible for 92% of the variance between assessments (Interpretation 35%, Information 27%, Criterion 25%, Observation 4%, and Recording 1%), while patient differences were associated with only 8% of the variance.5 Other assessments show similar proportions of unreliability.
That same year, the FDA advised using patient-reported outcomes (PRO) in Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Specifically, they stated:6
Use of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective.
It is difficult to conceive a SIB concept that wouldn’t be known best by the individual contemplating self-harm with potentially lethal consequences. Still, legitimate questions about the best methods for clinicians and PRO assessments of SIB remain. How should SIB be assessed? What are the consequences of clinicians changing or forgetting to ask questions? What happens if patients conceal responses or intentions?
The electronic PRO eC-SSRS, recognized by the FDA in 2012 as an acceptable assessment of suicide risk, addresses these issues straightforwardly. The eC-SSRS:
- Collects the critical subject/patient perspective directly
- Obtains greater candor regarding stigmatized suicide risk3
- Standardizes presentation of questions and follow-up queries (perfect procedural reliability)
- Records patient responses accurately (eliminates potential data entry errors)
- Documents completion of the SIB assessment
- Automatically alerts relevant personnel of risk-relevant responses
- Immediately generates reports of eC-SSRS results for clinician review
- Is constantly and conveniently available
- Stores data in real-time in a format ready for analysis
- Reduces assessment costs and staffing requirements
- Fully structured assessment = no missing data or rater variability
- Greater patient candor regarding suicidal ideation and behaviors (SIB)
- Clearest SIB questionnaire signal
- Findings report/alter is immediate for use in further clinician evaluation
- Prompt management of all results from eC-SSRS and clinician evaluation
- Saves staff time and costs less
- Ensures clearest assessment signal for patient safety
- Accurate signals of SIB also protect study medications
- Enables fast and informed decisions
- Costs reduced for clinicians and data management
1 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. Guidance for Industry Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials. In: Products DoP, ed. Revision 1 ed. Rockville, MD: Food and Drug Administration; August 2012.
2 Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277.
3 Greist JH. Greater Than “Even Greater” Need? J Clin Psychiatry. 2016;77(7):e902.
4 Mundt JC, Greist JH, Jefferson JW, et al. Prediction of Suicidal Behavior in Clinical Research by Lifetime Suicidal Ideation and Behavior Ascertained by the Electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry. 2013 Sep;74(9):887-93. doi: 10.4088/JCP.13m08398.
5 Kobak KA, Brown B, Sharp I et al. Sources of unreliability in depression ratings. J Clin Psychopharmacol. 2009 Feb;29(1):82-5. doi: 10.1097/JCP.0b013e318192e4d7.
6 U.S. Department of Health and Human Services FaDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH),. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims: US Food and Drug Administration; December 2009.