What Do the Changes in the FDA Suicidal Ideation and Behavior Guidance Mean for Sponsors?

In August, the FDA released its revised draft guidance for industry, Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials, which can be found online. To understand the nuances of the revisions compared to the September 2010 guidance, Applied Clinical Trials spoke with the following experts at ERT: John Greist, Consultant at ERT’s ePRO Solutions; Michael Federico, Vice President of ePRO Solutions; and Jean Paty, Chief Scientist and Regulatory Advisor, Outcomes at ERT.

These experts concur that FDAs changes were around clarifying the draft guidance, prior to a final guidance being released. While ERT points to a recent poll it did during a webinar that shows 47% of attendees were not aware of the guidance, these changes from FDA are instrumental to sponsors understanding and getting more specifics around assessing suicidal ideation and behavior in clinical trials.
The following six areas are what these experts conveyed as most important for the drug development community:

• Title change from suicidality, to Suicidal Ideation and Behavior

• Expansion of the C-CASA categories

• Types of drugs that warrant assessments

• Time burden of assessments

• Timing of assessments, and lifetime assessments

• Explicitly mentions the electronic Columbia Suicide Severity Rating Scale (eC-SSRS, which had not been mentioned in September 2010 guidance)

Greist said, “The two main goals of the prospective assessment are to identify patients at risk and help manage that risk and to collect complete timely data at the time the data are available rather than retrospectively trying to ferret them out of case report forms and adverse event reports which was so laborious. So that hasn’t changed a bit.”

In the area of C-CASA classification, Greist said the Guidance shifts from four of the nine previous C-CASA classifications to 11. Said Greist, “And 10 of those 11 are exactly the ones that are in the Columbia Suicide Severity Rating Scale, five for ideation, five for behaviors and then added as the 11th is the non-suicidal self-injurious behaviors. And to make that distinction from suicide attempt to non-suicidal self-injurious behavior is important and not easy.”

No Burden Increase, Says Data
What Greist also indicated was the use of data in the Guidance to allay concerns that assessment may be too much of a burden for the sites or for the subjects in the trials. In addition, the FDA is requesting a lifetime assessment that’s collected at baseline of real value in identifying patients who would have more behavior, suicidal behavior during the short term of the trial, and that also was addressed with data.
Greist said, “We learned from the electronic Columbia Suicide Severity Rating Scale in the first 35,000 assessments that the mean completion time was 3.8 minutes. It was 3.5 minutes for the 98.3% that in essence were negative assessments and only 7.7 minutes for the 1.7% of the assessments that had positive ideation or behavior. And the completion rate was 99.89%, which is the confirmation that the time burden from the patient perspective, from the site perspective is not great.”
Also, experts have asked how much benefit does lifetime assessment really provide? Greist says that from this group of 35,000 assessments, 6,000 were at baseline times and questioned lifetime ideation and behavior. “It found quite strikingly that those lifetime assessments did predict a substantial increase in the odds ratio between four and nine times, depending on which combination of ideation and behaviors were there. So it answered that question and FDA was pleased to have their expectation that the lifetime assessment would be valuable confirmed.”
As far as what types of drugs should be considered for suicidal ideation and behavior, the guidance outlined any drug for a psychiatric condition; epilepsy; and neurologic drugs with CNS activity (questions on that would go to the Division of Neurology Products); drugs that are pharmacologically similar to isotretinoin and other tretinoins, beta blockers (especially those entering the brain), reserpine, drugs for smoking cessation, and drugs for weight loss.

With that list of drugs that may offer signals, Federico offered that ERT doesn’t have hard data on sponsors increasing their monitoring of this. However, he did note in their experience with sponsors and their protocols in over 1,000 projects ERT is involved in on an ongoing basis, more of them have the suicide risk monitoring built into the protocol. “It’s really growing in its sponsor’s ability to write that into the protocol right upfront,” said Federico.
He continued, “As the guidance highlights, it needs to be done in every trial and at every visit, and that’s during the development process. We have seen a few that would be done after that fact, but most of the time it’s folks that are building this in through their Phase II and III development process leading up to a Summary of Safety for their NDA.”
According to Federico, ERTs solution in this area is an electronic C-SSRS, which is a patient self-rated prescreening via telephone at the site. The system is designed to branch and probe on each ideation and on each behavior that’s reported to get a time-efficient assessment, in a low burden way.
“We capture those responses immediately and are able to respond to the site to remind them, if we did get a positive outcome, that they need to read and respond to that report before they let the patient leave the office,” explained Federico.
In mental health settings, Federico says they are fairly comfortable with this particular scale and the self-rated prescreening that the report delivers. “However, if we’re in a non-mental health setting, the report that we deliver to the site enables them to have the confidence that the interview was done correctly and to be able to use the responses in the report to review with the subject, if need be, and get a mental health consultation if that’s what’s required in their protocol.”
Paty, who has worked on developing real-time, real-world solutions to study the patient experience since 1990, and was co-founder of invivodata, a PRO/ePRO service provider, which was purchased by ERT this past July, said: “We’re excited to be part of this. We’re really pleased to see FDA define a guidance to provide for the direction to industry, especially on such a key topic. I mean, as a clinical psychologist myself, and John Greist has far more experience than me, when we have a patient in front of us that we see a positive signal for a suicide ideation and behavior, this is a very serious matter. And so we’re pleased, as part of the industry, to be part of this effort and just fully support and endorse FDA’s work here.”

Visit

a slideshow podcast related to this interview.