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Assessing Suicide Risk

The US FDA regulatory Guidance on Suicidal Ideation and Behaviour has been reviewed and re-released as study teams are concerned with patient safety, regulatory compliance and reducing site burden.

Increasing concern regarding treatment-emergent suicidality in clinical trials has prompted a Guidance Document on Prospective Assessment of Suicidal Ideation and Behaviour (SIB) from the US FDA. First released in September 2010 and modified in August 2012, the FDA’s revised draft guidance brings more clarity to the expectations of when, where and how to assess SIB. The recommended application is as broad as its goals: firstly, to ensure that patients in clinical trials who are experiencing suicidal ideation and behaviour are properly recognised and treated; and secondly, to ensure the collection of more timely, more complete and more reliable data. In particular, the assessment of SIB is required in clinical trials of new drugs being developed for psychiatric indications and any drug that appears to have an effect on the CNS. This includes trials in other areas such as epilepsy, smoking cessation and weight-loss, due to long-standing concerns with SIB in these study populations.

The Columbia-Suicide Severity Rating Scale (C-SSRS), a freeform clinician-administered interview, is an accepted instrument to monitor SIB. However, procedural variance in the way these clinical assessments are performed by human raters has been a shortcoming for many years, negatively impacting the reliability of results. Electronic patient reported outcomes (ePRO) solutions can effectively address this limitation. The eC-SSRS, a self-rated electronic version of the C-SSRS is a fully structured, validated interview. Since its introduction, it has been incorporated into many sponsored clinical trials and used in over 52,000 interviews. This article provides an overview of the revised FDA draft guidance, the limitations of the C-SSRS and the benefits of the eC-SSRS in meeting this FDA requirement.

Monitoring Scope

The need for the monitoring of suicidal ideation and behaviour in clinical trials is increasingly recognised as a vital safety requirement. This includes, but is not limited to, studies of psychiatric conditions, epilepsy, neurologic drugs, drugs that are pharmacologically similar to isotretinoin and other tretinoins, beta blockers, and any other compounds with CNS activity – especially those entering the brain, such as reserpine and drugs for smoking cessation and weight loss. This assessment has not proven to be a significant time burden, and assessments are necessary to ensure patients are free from risk when participating in trials. As a result of the review and comments on the first draft, the FDA has recently released a revised version of its initial 2010 guidance on this topic.

Regulatory Analysis

Initially released in 2010, the draft guidance represented the FDA’s current thinking regarding the assessment of treatment-emerging suicide. The guidance is marked with objectives to ensure prompt recognition and treatment of at-risk patients. It is also designed to facilitate more complete and timely data collection, as well as to limit spurious signals, risks and concerns arising from spontaneous reports. The 2012 revised draft guidance identifies no fundamental policy shifts, but instead reinforces and clarifies the original objectives – patient safety and quality of data. The FDA guidance brings more clarity to the expectations of when, where and how to assess SBI. It also cites data showing that assessment is low burden to the patient and recognises the value of lifetime assessments in providing protection for patients at risk.

According to the guidance, a suicidality assessment instrument must map 11 SIB codes – five ideation, five behaviour and one for non-suicidal self-injurious behaviour. These represent the prospective finding counterpart to the retrospective Columbia Classification Algorithm of Suicide Assessment (C-CASA). The C-SSRS is an accepted instrument used to assess the suicidal ideation of trial participants. It is essentially a semi-structured interview designed to be conducted with subjects during trials, at baseline and at each patient visit. The scale probes and documents the patient’s possible suicidal ideation and behaviours into a set of results that directly code to those noted in the guidance.

Assessing ePRO Solutions

Although the C-SSRS is an accepted instrument for meeting regulatory requirements, it does present a number of limitations when employing human assessment methods, stemmed from the long-standing concern with procedural variability and clinical reliability of assessments by human raters. Even with extensive training, rater skills deteriorate over time and clinicians can be influenced by patient experiences, thus decreasing the reliability and accuracy of suicidal assessments. This is combined with the problems of obtaining truthful patient responses, with recent studies demonstrating that patients tend to disclose more suicidal thoughts and behaviours to non-human computer interviewers than to clinicians during an interview (1).

In response to this, ePRO technology has demonstrated feasibility and clinical validity for monitoring suicidality, while enabling clinical trial investigators to eliminate data collection issues, such as clinician bias, processing delays and the monitoring of sensitive patient data. In addition to this, high quality data can be gathered without the need for third-party involvement, offering superior confidentiality.

Owing to their unique advantages, ePRO solutions have traditionally been employed to support key aspects of the clinical trial process, including subject recruitment, patient diaries, clinical assessments and safety monitoring and alerting. The FDA cited technology encompasses a wide range of tools, including interactive voice response (IVR), personal digital assistant (PDA), web browser-based and mobile phone-based solutions. The list selection/answer format typical of the C-SSRS allows ease of use, and patient responses are obtained, checked for validity and stored in an electronic database. In addition to the associated technology benefits, ePRO systems promote compliance reminders for medication, completion of diary entries and data submission.

The eC-SSRS

The FDA draft guidance specifies that alternative methods for administering the C-SSRS, including self-reporting using telephones or computers, are appropriate if validated. Adhering to these guidelines, a structured C-SSRS script with standardised probes, error handling, appropriate follow-up queries and assessment scoring conventions has been developed for audio and display administration of an electronic C-SSRS, the eC-SSRS.

The eC-SSRS is a fully structured version of the C-SSRS interview, designed for computer administration directly by patients using IVR or web technology. The tool streamlines the data collection process and facilitates the collection of high quality, unbiased data directly from the patient while eliminating processing delays.

Clinical assessment questions are presented and patients provide their responses, which then enables the system to branch to the appropriate follow up questions, faithfully adhering to C-SSRS probing specifications. These findings are registered, scored, and a report is immediately sent for site review. Contrary to traditional interview techniques, the eC-SSRS programme uses specific algorithms to ensure that all relevant questions are asked in a consistent manner and backed by a complete ePRO solution.

The eC-SSRS system can reliably and accurately identify changes in suicidality signals enabling swift reaction to suicide concerns to ensure patient safety. Telephone-based systems, such as IVR, are simple and enable patients to report their feelings without any additional equipment to manage. Subjects use a toll-free number and enter their responses using the familiar telephone keypad. This data then goes directly into the vendor’s central database making the process simple, convenient and immediate.

It is important to note that this approach is not intended to replace clinical judgement, but to provide clinicians with useful unbiased information for exercising clinical discretion regarding patient safety. Clinician judgement can be combined with the eC-SSRS for immediate, automated, standard reports of patient response in order to facilitate precise, efficient and thorough assessment of suicidal ideation and behaviour. The eC-SSRS has now been used successfully to perform over 52,000 interviews across a variety of geographies due to its simple, adherence prompting, non-intrusive method of reporting.

Conclusion

The recent heightened concerns over the increased risk of suicidal ideation and behaviour in clinical trial participants has led to the publishing of the newly revised guidance from the FDA, ‘Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials’. The guidance highlights that it is essential that drug development programmes consider using progressive, yet efficient approaches to incorporate this assessment into clinical trials.

Not only will implementing C-SSRS assessments ensure patient safety and reduce site burden, it will also protect new compounds from false positive findings due to incomplete assessment. Although the assessment is not mandatory in most trials, it is now recommended by regulatory bodies and industry figures, who strongly suggest that these types of assessments are conducted in drug development programmes with CNS involvement.

Citing the innovative eC-SSRS as a solution to achieving reliable, high quality data, the technology is now being used to overcome the shortcomings associated with traditional, paper/clinician-based assessments. The eC-SSRS provides sponsors with a fast and dependable means of collecting valuable information relating to the welfare and safety of patients and ultimately allows swift and effective interventions for at-risk subjects.

Reference
  1. Trivedi et al, J Clin Psychiatry 72; pp757-764, 2011


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Michael Federico is Vice President of ePRO solutions at ERT and is responsible for managing all aspects of the ePRO Solutions suite, including product development, operations and sales. Prior to joining ERT, Michael spent over 20 years in systems design, evaluation and equipment management in the healthcare field. 

 
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