Discover More: Prospective Assessment of Suicidal Ideation and Behavior in Clinical Studies
We will begin our journey together by discussing the prospective assessment of suicidal ideation and behavior in clinical studies. This article is based on an interview with Dr. John Greist, CEO of Healthcare Technology Systems, a board certified psychiatrist, and one of the creators of the electronic Columbia Suicide Severity Rating Scale (eC-SSRS). If you are interested in viewing Dr. Griest introduce himself and this article, view the video below.
First, let’s set the stage for the draft guidance. Certain medications were found to have an increased effect on suicidal ideas and behavior. As the FDA became aware of this issue, they reviewed data from trials in several therapeutic areas to see whether the medications might have contributed to this adverse side effect. With some medications, small but clear increases in suicidal thoughts and behaviors were found with cumbersome retrospective data extraction from case report forms for meta-analyses, leading to boxed warnings for anti-depressants and other warnings for other classes of medications, such as anti-epileptic drugs. Other concerns had emerged from spontaneous reports regarding some weight loss, smoking cessation, dermatologic and other drugs affecting the Central Nervous System. Suicidal ideation and behavior are seen by some as the mental health equivalent of liver function abnormalities or cardiac arrhythmias caused by some medications.
In September 2010, the FDA released the draft guidance “Suicidality: Prospective Assessment of Occurrence in Clinical Trials”. Prospective assessments are more reliable and accurate, less burdensome to acquire and analyze, and less subject to bias than retrospective evaluations. It is intended that prospective assessment will cap concerns about suicidal ideation and behaviors associated with medications, as well as help identify medications with specific anti-suicidal effects, whether as a primary indication or as a beneficial side effect of other main effects for which the drugs and their claims are developed. Comments regarding the guidance were collected and the FDA is now preparing to produce either another draft guidance regarding suicidality safety monitoring or proceed to a final guidance document.
The Columbia group that performed the retrospective evaluations for the FDA developed the Columbia Suicide Severity Rating Scale (C-SSRS) as a prospective assessment tool and, at present, that is the only instrument described as acceptable in the draft guidance. The draft guidance did indicate however, that other assessments may be acceptable, if properly validated, including comparison with the C-SSRS.
After refinement of the C-SSRS, the eC-SSRS (electronic Columbia Suicide Severity Rating Scale) was created. Using interactive voice response technology (IVR), the eC-SSRS is an electronic and self-rated approach to administering the C-SSRS that has been shown to reliably assess suicidal ideation and behavior in clinical trials. That work involved Dr. Kelly Posner of Columbia University, a primary author of the C-SSRS, Drs. John Greist, James Mundt and Alan Gelenberg of HTS and ERT’s ePRO Solutions team. The 6 month collaboration ensured the wording and branching between questions and sub questions were equivalent to the paper-based C-SSRS modality. The eC-SSRS has now been in use for just over one year and more than 23,000 assessments have been successfully performed using this solution.
The eC-SSRS compliments the C-SSRS yet can provide some additional benefits such as patient privacy in this stigmatized area. Patients often want doctors to know of suicidal ideation and behavior but find it difficult to disclose this kind information, just as they find it difficult to disclose other sensitive kinds of information about sexual functioning, substance abuse or HIV risk factors. Since patients tend to disclose more in a computer interview than they do in a face to face human interview, there is a decrease in false negative reports (Type II error), increasing patient safety. Patients also like the fact that the interview goes at their pace and they don’t feel pressured working with obviously busy clinicians. Patients can back up to reconsider a question or change their answer. In essence, the interview doesn’t boss the patient, instead responding appropriately and guiding them through the assessment easily and at a comfortable pace.
Another significant benefit is that the burden of assessment is largely removed from site personnel. Medical staff only need to conduct in depth follow up when the eC-SSRS has positive results, which has occurred in less than 1.5% of all assessments. Clinicians can then focus their attention and bring to bear their knowledge, experience and intuition where it is most needed, rather than in repetition of an assessment where over 98% are negative. Also, the data are immediately in electronic form, eliminating almost all post assessment queries. Ultimately, the eC-SSRS produces clean data having documented every question and answer, helps protect patient safety, encourages greater patient disclosure, and reduces site and sponsor burdens.
Despite the benefits associated with the eC-SSRS, sponsors should choose which prospective assessment tool to use based on scientific data, patient safety, site and sponsor burden, as well as cost. For small Phase I studies, the cost of setting up a computer system could be too great to warrant its use, but evaluation of this cost / benefit equation costs nothing and evaluation of the potentially significant return on investment is encouraged. Another factor is the availability of translations for international studies with translations increasing rapidly to address this issue. For most phase II, III and IV studies the benefits of the eC-SSRS make it the preferred choice. It is helpful that some assessments may be performed with the eC-SSRS and others with the C-SSRS within the same development program, under the same protocol and even at the same site.
Sponsors have been positive about the FDA guidance, recognizing that it is FDA’s responsibility to ensure that medications are as safe and effective as possible before they are released. It has been impressive to see how quickly the Pharmaceutical industry has responded to the issues of increased suicidal ideation and behavior from certain medications and have recognized the need to define, in the best way possible, any suicidality risk associated with new medications. Recognition is growing that not only psychiatric disorders, where suicide is often considered, are in need of prospective assessment for suicidality. Potentially any neurological medications that have central nervous system effects may, but hopefully will not, have these dangerous side effects. Prospective assessments are also intended to identify medications that do not have these adverse attributes and even medications that reduce risk of suicide. For researchers, regulators, clinicians, sponsors, and especially patients, properly assessing suicide is a critical step in their development and use.
Please feel free to leave any questions or comments regarding this topic for Dr. Greist or ERT and we will ensure a prompt response. Thank you for being a part of the ERT community!