Guidance for Industry 

Suicidal Ideation and 

Behavior:  Prospective 

Assessment of Occurrence in 

Clinical Trials 

 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact Thomas Laughren at 301-796-2260.    
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
August 2012 

Clinical/Medical 

 
Revision 1 

 
10302dft.doc 
 
08/06/12   
Guidance for Industry 

Suicidal Ideation and 

Behavior:  Prospective 

Assessment of Occurrence in 

Clinical Trials 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
August 2012 

Clinical/Medical 

 
Revision 1 

 
   
TABLE OF CONTENTS 

 
I.	   INTRODUCTION............................................................................................................. 1 
 
II.	   BACKGROUND ............................................................................................................... 2 
 
III. 	  PROSPECTIVE ASSESSMENT OF SUICIDAL IDEATION AND 

BEHAVIOR OCCURRENCE  GENERAL RECOMMENDATIONS ................... 3 
 
A.   Suicidal Ideation and Behavior Assessment Instruments...........................................................3
  
B.   Managing Suicidal Ideation and Behavior Data..........................................................................6
  
C.   Specific Trial Considerations ........................................................................................................7
  
1.  Identifying Trials in Which Suicidal Ideation and Behavior Assessment Should be 
 
Carried Out ......................................................................................................................................7
  
2.  Populations in Which Assessment of Suicidal Ideation and Behavior Would be Difficult...............7
  
3.  Dosing Considerations.....................................................................................................................8
  
a.   Single-dose trials.......................................................................................................................8
  
b.   Microdose trials ........................................................................................................................8
  
4.  Timing of Assessments......................................................................................................................8
  
5.  Implementation During Ongoing Trials...........................................................................................9
  
6.  Prospective Assessments in Large Simple Trials .............................................................................9
  
IV. 	  PROSPECTIVE ASSESSMENT OF SUICIDAL IDEATION AND 

BEHAVIOR OCCURRENCE  SPECIFIC INDICATION 

RECOMMENDATIONS.................................................................................................. 9 
 
REFERENCES............................................................................................................................ 11 
 
APPENDIX A:  SUICIDAL IDEATION AND BEHAVIOR CATEGORIES AND 

DEFINITIONS ............................................................................................................................ 12 
 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1 
Guidance for Industry  
1 
Suicidal Ideation and Behavior:  Prospective Assessment of 
2 
Occurrence in Clinical Trials 
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
9  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
10  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
11  the applicable statutes and regulations. If  you want to discuss an alternative approach, contact the FDA 
12  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
13  the appropriate number listed on the title page of this guidance. 
14   
15   
16   
17   
18  I.  INTRODUCTION  
19   
20  The purpose of this guidance is to assist sponsors in prospectively assessing the occurrence of 
21  treatment-emergent suicidal ideation and behavior in clinical trials of drug and biological 
22  products.2  The focus of this guidance is on clinical trials conducted under investigational new 
23  drug applications, or trials that are intended for submission in a new drug application or a 
24  biologics license application. Specifically, this guidance addresses the Food and Drug 
25  Administrations (FDAs) current thinking regarding the importance of assessment of suicidal 
26  ideation and behavior in psychiatric and nonpsychiatric drug trials falling under the authority of 
27  the FDA, and the general principles for how best to accomplish this assessment during drug 
28  development.  This guidance is not intended to give advice on how best to screen patients for 
29  entry into clinical trials, even though instruments used for assessing patients during the conduct 
30  of trials can also be used for screening patients.  Making decisions about which patients to enter 
31  into a particular trial is a separate matter that is determined largely by the questions that the trial 
32  is intended to address. 
33   
34  The principles discussed in this guidance for the prospective assessment of suicidal ideation and 
35  behavior involve actively querying patients about the occurrence of suicidal thinking and 
36  behavior, rather than relying on patients to report such occurrences spontaneously, followed by 
37  retrospective classification of events into appropriate categories.  This guidance offers advice 
38  about criteria that should be met for a suicidal ideation and behavior assessment instrument that 
39  can be used to conduct such prospective assessments. 
40   
                                                 
1 This  guidance has been  prepared by the Division of Psychiatry Products in  the Center for  Drug Evaluation and  
Research (CDER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified. 
1 
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Draft  Not for Implementation  
41  This guidance is intended to serve as a focus for continued discussions among the FDA, 
42  pharmaceutical sponsors, the academic community, and the public.3  This guidance does not 
43  address the complex analytic issues involved in the analysis of the suicidal ideation and behavior 
44  data that will be derived from prospective assessments of suicidal ideation and behavior; these 
45  issues will be addressed in a separate guidance. 
46   
47  This guidance revises the draft guidance for industry Suicidality: Prospective Assessment of 
48  Occurrence in Clinical Trials issued in September 2010.  This revision: 
49   
50     Replaces the term  suicidality with the phrase suicidal ideation and behavior  
51   
52     Provides an expanded set of the Columbia Classification Algorithm for Suicide 
53  Assessment (C-CASA) categories, along with definitions and explanations 
54   
55     Revises the advice on particular trials and patients that would need assessments of 
56  suicidal ideation and behavior, and the timing of such assessments 
57   
58     Addresses concerns about the time burden of assessments  
59   
60     Addresses questions about the possible value of the assessments providing protection for 
61  patients in the trials themselves  
62   
63     Makes it clear that use of an assessment instrument that directly classifies relevant 
64  thoughts and behaviors into C-CASA categories eliminates the need for any additional 
65  coding 
66   
67     Provides multiple additional references 
68   
69     Revises advice on evaluation of alternative instruments 
70   
71  FDAs guidance documents, including this guidance, do not establish legally enforceable 
72  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
73  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
74  cited. The use of the word should in Agency guidances means that something is suggested or 
75  recommended, but not required.   
76   
77   
78  II.  BACKGROUND 
79   
80  There has been a great deal of attention paid to treatment-emergent suicidal ideation and 
81  behavior in recent years, and to the question of how best to assess these types of events in future 
82  trials. The attention has resulted in part from  findings of apparent treatment-emergent suicidal 
83  ideation and behavior caused by several different types of drugs.  Meta-analyses of placebo-
                                                 
3 In addition to consulting  guidances, sponsors are encouraged to contact the relevant  review division to  discuss 
specific issues that arise during the development of specific drugs.  
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
84  controlled antidepressant trials, both pediatric (Hammad, Laughren, et al. 2006) and adult (Stone, 
85  Laughren, et al. 2009), revealed a signal for drug-related treatment-emergent suicidal ideation 
86  and behavior at the younger end of the age spectrum.  A meta-analysis of placebo-controlled 
87  trials of antiepileptic drugs, including drugs with diverse pharmacology in studies of epilepsy as 
88  well as psychiatric indications, also revealed a signal for drug-related treatment-emergent 
89  suicidal ideation and behavior.4  In all of the trials in these meta-analyses, the suicidal ideation 
90  and behavior events were identified and classified retrospectively; that is, the trials were not 
91  designed to identify such events prospectively.  Perhaps as a result, relatively few cases were 
92  identified in this effort, the case descriptions were not complete, and baseline status was not 
93  well-defined. 
94   
95  The concern about treatment-emergent suicidal ideation and behavior has arisen for other drugs 
96  as well, based largely on spontaneous reports and published case reports.  Drugs with such 
97  reports have included isotretinoin and other tretinoins, beta blockers, reserpine, smoking 
98  cessation drugs, and drugs for weight loss. In view of the wide range of drugs involved, it is 
99  reasonable to consider whether prospective assessments for suicidal ideation and behavior should 
100  be included in clinical trials involving at least selected drugs for nonpsychiatric indications.   
101   
102  There are two reasons for prospectively assessing suicidal ideation and behavior in clinical trials.  
103  The first is to ensure that patients in clinical trials who are experiencing suicidal ideation and 
104  behavior are properly recognized and adequately treated.  The second is to ensure the collection 
105  of more timely (i.e., closer to the event) and more complete data on suicidal ideation and 
106  behavior than have been collected in the past, so that increased suicidal ideation and behavior in 
107  individual trials and in pooled analyses are easier to detect.  This is important whether or not a 
108  particular drug is known to be associated with treatment-emergent suicidal ideation and 
109  behavior. Collection of such data will also provide scientifically sound evidence to evaluate 
110  concerns about a possible association with suicidal ideation and behavior for a drug that is based 
111  only on individual case reports. 
112   
113  The following sections provide general recommendations for prospective assessment of the 
114  occurrence of suicidal ideation and behavior, applicable to any drug, followed by a discussion of 
115  which drugs should be assessed for suicidal ideation and behavior in addition to drugs for 
116  psychiatric indications. 
117   
118   
119  III.   PROSPECTIVE ASSESSMENT OF SUICIDAL IDEATION AND BEHAVIOR  
120  OCCURRENCE  GENERAL RECOMMENDATIONS 
121   
122  A.  Suicidal Ideation and Behavior Assessment Instruments 
123   
124  The Columbia-Suicide Severity Rating Scale (C-SSRS),5 one of several available suicidal 
125  ideation and behavior instruments, defines five subtypes of suicidal ideation and behavior that 
                                                 
4 See the Suicidal Behavior and Ideation and Antiepileptic  Drugs FDA Web page at  
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM100190. 
 
5 See http://www.cssrs.columbia.edu.  
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126  we consider important to capture in any prospective assessment.  In addition, we believe it is 
127  useful to capture instances of self-injurious behavior with no suicidal intent, because it is 
128  important to distinguish these behaviors from actions with suicidal intent.  The ability to make 
129  this distinction helps ensure that what is labeled as a suicide attempt does in fact meet criteria for 
130  such a designation. Thus, the current preferred terms that we consider important include five 
131  levels of suicidal ideation, five levels of suicidal behavior, and the category self-injurious 
132  behavior, no suicidal intent. We have adopted these 11 categories as the standard for classifying 
133  suicidal ideation and behavior events.  These categories are defined in Appendix A.  It should be 
134  noted that the definitions provided for the five levels of suicidal behavior have been adopted by 
135  the Centers for Disease Control and Prevention (Crosby, Ortega, et al. 2011).  
136   
137     Suicidal ideation 
138  1.   Passive 
139  2.   Active: Nonspecific (no method, intent, or plan) 
140  3.   Active: Method, but no intent or plan 
141  4.   Active: Method and intent, but no plan 
142  5.   Active: Method, intent, and plan6  
143   
144     Suicidal behavior 
145  1.   Completed suicide 
146  2.   Suicide attempt 
147  3.   Interrupted attempt 
148  4.   Aborted attempt 
149  5.   Preparatory actions toward imminent suicidal behaviors   
150   
151     Self-injurious behavior, no suicidal intent   
152   
153  We recommend use of a suicidal ideation and behavior assessment instrument that directly 
154  classifies suicidal ideation and behavior into the 11 preferred categories, defined in Appendix A.  
155  As stated above, the C-SSRS is a prospective assessment instrument that directly classifies 
156  suicidal ideation and behavior into these 11 preferred categories,7 and this instrument would be 
157  acceptable for the purpose of these studies.  The C-SSRS involves a series of probing questions 
158  to inquire about possible suicidal thinking and behavior, and this process is conducted at baseline 
159  (this would be a lifetime suicidal ideation and behavior assessment) and at each patient visit.  
160  Although completion of the C-SSRS is, in many instances, based entirely on the patient 
161  interview, it also allows for integration of information from  other sources (e.g., family, friends, 
162  or significant others; caregivers or health professionals; hospital or emergency room records; 
163  coroners report or death certificate).  In fact, the C-SSRS is not considered complete for any 
164  particular visit until information from all potential sources has been evaluated and integrated.   
165   
166  Important psychometric properties of the C-SSRS have been established and reported in several 
167  papers. A recent paper reported on the instruments construct validity (its ability to detect  
                                                 
6 According to  C-SSRS, the definition of plan includes intent (i.e., intent to complete the suicide is implicit with the 
concept  of plan).  Thus, there is no  need for the category  method and plan,  but no  intent.  (See Appendix  A.)   
 
7 See http://www.cssrs.columbia.edu.  
4 
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168  suicidal ideation and behavior) based on correlation with other measures of suicidal ideation and 
169  behavior assessed in three multisite clinical trials (Posner, Brown, et al. 2011).  The instrument 
170  performed well relative to other instruments, and had high sensitivity and specificity of suicidal 
171  behavior classifications relative to another behavior instrument and to assessments by an 
172  independent suicide evaluation board.  Inter-rater reliability for the C-SSRS has been well-
173  established in earlier studies (Pumariega, Millsaps, et al. 2011; Brent, Greenhill, et al. 2009). 
174   
175  The information pertinent to suicidal ideation and behavior collected in the C-SSRS interview is 
176  classified into the set of 11 preferred categories described above as the interview is conducted.  
177  The direct classification of information collected in the C-SSRS interview into these 11 
178  categories, along with integration of information about the event from other sources, renders it 
179  unnecessary to conduct any other classification step (i.e., this process replaces the retrospective 
180  classification of data that was needed for the FDAs meta-analyses of suicidal ideation and 
181  behavior). For example, after it is determined, based on the C-SSRS interview and information 
182  from other sources, that a potentially self-injurious event was an actual suicide attempt, this fact  
183  is noted on the C-SSRS form, and no further classification is needed.  It is important to note that 
184  the C-SSRS form is not complete until all available relevant data have been accessed and 
185  integrated into the assessment.  Data entries for C-SSRS classified events then become the basis 
186  for analyses of future trials focused on suicidal ideation and behavior.   
187   
188  The C-SSRS is a detailed interview, but the full interview is needed only if the initial screening 
189  questions about suicidal ideation and behavior are positive.  Although the screening questions 
190  should be completed at baseline and at every visit for every patient, they are not by themselves 
191  burdensome, typically taking only 1 to 2 minutes for patients who have no positive findings.  
192  Even for a patient with multiple positive findings, the full interview typically takes less than 10 
193  minutes.  Data from almost 15,000 administrations of an electronic self-report version of the C-
194  SSRS (i.e., the eC-SSRS) found an average completion time of 3.5 minutes for patients without 
195  positive findings, and about 7 to 8 minutes for patients with positive findings (Mundt, Greist, et 
196  al. 2010a). The eC-SSRS uses probe questions similar to those used by a human interviewer in 
197  the paper form of the C-SSRS. It is an alternative approach to obtaining data on suicidal ideation 
198  and behavior (Mundt, Greist, et al. 2010b).  
199   
200  The following information can be used by sponsors to evaluate the appropriateness of other 
201  proposed instruments:  
202   
203     Categories: The instrument ideally should include all the categories of suicidal ideation 
204  and behavior identified in the 11 preferred terms defined in Appendix A.   
205   
206     Definitions: The instrument should include definitions for all of these categories (these 
207  definitions ideally should coincide with the definitions in Appendix A).   
208   
209     Probes/Questions: The instrument should include probes or questions that permit 
210  determination of whether or not each of these ideas or behaviors occurred. 
211   
212     Other information: The instrument should provide for integration of information from 
213  other sources (e.g.,  family, friends, or significant others; caregivers or health 
5 
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Draft  Not for Implementation  
214  professionals; hospital or emergency room records; coroners report or death certificate)  
215  to permit accurate completion of the assessment.   
216   
217     Direct classification into the 11 preferred terms (see Appendix A): Use of the C-SSRS 
218  instrument accomplishes this goal directly, and other instruments used for this purpose 
219  ideally would be capable of doing this as well.  Other instruments that do not accomplish 
220  this classification directly can still be useful for the purpose of protecting patients in a 
221  trial. In these instances, however, it may not be possible to use data from these trials in 
222  future meta-analyses exploring for treatment-emergent suicidal ideation and behavior in 
223  multiple treatment programs.  
224   
225     Training: There should be provisions for formal training of raters to ensure accuracy 
226  and consistency in application of the instrument. 
227   
228  Although we consider the C-SSRS an acceptable prospective suicidal ideation and behavior 
229  assessment instrument, other instruments, as noted above, could also be acceptable if they 
230  directly classify events of interest into the 11 categories of suicidal ideation and behavior 
231  described above. Sponsors should, however, discuss the acceptability of alternative instruments 
232  with the FDA before using them in clinical trials.  Although alternative instruments could be 
233  acceptable, it should be noted that the use of different assessment instruments in different 
234  programs is likely to increase measurement variability across programs, decreasing the 
235  opportunity to identify potential signals in future meta-analyses that include data from multiple 
236  programs.  This type of imprecision is particularly problematic in dealing with events that have a 
237  low incidence, as is the case for suicidal ideation and behavior occurring in clinical trials.   
238   
239  B.  Managing Suicidal Ideation and Behavior Data 
240   
241  This section provides general advice regarding management of data from prospective 
242  assessments of suicidal ideation and behavior in clinical trials.  Detailed advice about the 
243  structure of data tables and other data recommendations for preparing a suicidal ideation and 
244  behavior submission to the FDA will be addressed in a separate guidance, as will analytic and 
245  statistical considerations. Although a composite of suicidal ideation and behavior was the 
246  primary endpoint in previous FDA meta-analyses, it is likely that future meta-analyses will 
247  consider suicidal behavior and ideation separately, because they may have different predictive 
248  value for subsequent suicidal behavior. 
249   
250  We believe that an important feature of an instrument used for prospective assessment of suicidal 
251  ideation and behavior, especially with regard to future meta-analyses, would be that it directly 
252  classifies events of interest into the 11 categories of interest as part of the assessment process.  
253  Such instruments would not require the creation of narratives for blinded assessment of suicidal 
254  ideation and behavior by experts, as was the case for previous FDA meta-analyses.  The 
255  databases generated from use of the C-SSRS or other assessment instruments judged to be 
256  acceptable for this purpose would serve directly as the basis for any subsequent analyses.   
257   
258  It is possible for a patient to have more than one type of event during an interval.  For example, 
259  during a reporting interval, a patient might have experienced separate instances of suicidal 
6 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
260  ideation, self-injury without suicidal intent, suicide attempt, and completed suicide.  We 
261  acknowledge that it is often difficult to determine whether a sequence of such events represents a 
262  continuum of related events, in which case it would be most reasonable to classify such a 
263  continuum according to the most serious event, or whether these are really distinct events, in 
264  which case it would be reasonable to consider them separately.  This is a judgment best made by 
265  the interviewer, or if a self-reporting approach is used, by the patient.  If the events are discrete, 
266  they can still be captured in a single C-SSRS interview and rating form.  In previous meta-
267  analyses, we counted only the most serious suicidal ideation or behavior event during an interval, 
268  and this may still be the optimal approach.  Nevertheless, different approaches might also be 
269  used in future analyses. Consequently, all events that can be determined to be discrete events 
270  should be separately classified and recorded for the interval being assessed.   
271   
272  C.  Specific Trial Considerations 
273   
274  1.  Identifying Trials in Which Suicidal Ideation and Behavior Assessment Should be 
275  Carried Out 
276   
277  In general, suicidal ideation and behavior should be assessed in every trial after it has been 
278  determined that the drug is appropriate for this assessment (see section IV).  The full assessment 
279  of suicidal ideation and behavior generally should involve a pooled analysis of all controlled 
280  trials, so that it will not be possible to conclude that a drug has no effect on suicidal ideation and 
281  behavior until a substantial database is available for this analysis.  A separate guidance on 
282  statistical issues involved in the analysis of suicidal ideation and behavior will address general 
283  principles to consider in reaching a judgment on this issue.  Sponsors who believe they have 
284  sufficient data to address this issue should seek advice from the relevant review division.   
285   
286  2.  Populations in Which Assessment of Suicidal Ideation and Behavior Would be 
287  Difficult 
288   
289  It is reasonable to omit, or consider alternative assessments in, trials involving patients with 
290  cognitive impairment so substantial as to interfere with an understanding of the concept of 
291  suicide. Such populations can include certain patients with Alzheimers disease (those with 
292  severe cognitive impairment), other dementias, mental retardation, and autism. Critically ill 
293  patients would also be difficult to assess for suicidal ideation and behavior.   
294   
295  Instruments such as the C-SSRS have been used successfully in children and adolescent patients 
296  with various psychiatric disorders that do not involve cognitive impairment.  Nevertheless, 
297  assessing young children also can be challenging because many may not have reached sufficient 
298  cognitive maturity to understand the concept of death.   
299   
300  A sponsor considering the omission of standard suicidal ideation and behavior assessments 
301  (where these generally would be conducted) from a specific clinical trial in a particularly 
302  challenging population should discuss this omission with the review division to obtain prior 
303  agreement.  In certain instances, alternative instruments may permit the assessment of suicidal 
304  ideation and behavior or other adverse psychological events.     
305   
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306  3.  Dosing Considerations 
307   
308  a.  Single-dose trials 
309   
310  Because the time course of the risk for drug-induced suicidal ideation and behavior is unknown 
311  and likely differs by drug or drug class, it cannot be assumed that short-term trials pose no risk to 
312  patients and healthy volunteers. However, treatment-emergent suicidal ideation and behavior 
313  have rarely been reported in relatively short-term multiple-dose phase 1 trials in healthy 
314  volunteers. The risk of such an event would be even lower in single-dose trials in healthy 
315  volunteers. In addition, such trials are generally conducted in well-controlled settings with 
316  almost continuous observation, so that any treatment-emergent events would be readily detected.  
317  Therefore, we have concluded that multiple-dose trials in healthy volunteers should include such 
318  assessments, but that it is reasonable to omit such assessments from single-dose trials in healthy 
319  volunteers. 
320   
321  b.  Microdose trials 
322   
323  It is reasonable to omit suicidal ideation and behavior assessments in microdose trials involving 
324  low doses that are not expected to have any measurable pharmacological effects.  Microdose 
325  trials are typically employed for imaging agents in the assessment of receptor occupancy.   
326   
327  4.  Timing of Assessments 
328   
329  In general, in outpatient trials for which assessment of suicidal ideation and behavior are 
330  considered appropriate, assessments should be conducted at baseline (the lifetime suicidal 
331  ideation and behavior assessment) and at all planned visits at which other clinical assessments 
332  are to be carried out.8  For certain drugs (e.g., those with particularly long elimination half-lives), 
333  it may make sense to include follow-up assessments even after dosing has stopped.  These 
334  assessments should also be conducted at any unplanned visits at which other clinical assessments 
335  are needed. 
336   
337  Determining what constitutes a visit generally is straightforward for an outpatient trial, but not 
338  necessarily for an inpatient trial.  For an inpatient trial, suicidal ideation and behavior 
339  assessments ordinarily would be done at the same times as other symptom assessments, but 
340  would not be needed at the times of nonsymptom assessments (e.g., vital signs).  Sponsors 
341  should seek advice from the review division if there are questions about the appropriate 
342  frequency and timing of assessments for particular trials.   
343   
                                                 
8 Some have argued that there is no evidence that these types of assessments in the context of clinical trials provide 
any protection for patients in these trials, but  are only  useful for making population decisions about  drugs over  
relatively long  periods of time.   Although earlier trials looking at suicidal ideation overall (without regard to 
severity) did not find evidence for the predictive value of  detecting ideation  for suicidal behavior over the short-
term, two recent analyses from  independent sources found that severity of suicidal ideation detected in baseline C-
SSRS assessments predicted suicidal behavior  over a relatively brief  follow-up period  (Posner, Brown,  et al. 2011; 
Mundt, Posner, et al. 2011).  These recent findings support the use of assessments for suicidal ideation and behavior 
in clinical trials as a way of providing additional protection for patients in  the context of such trials.   
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344  5.  Implementation During Ongoing Trials 
345   
346  Determining how to implement suicidal ideation and behavior assessments in ongoing trials may 
347  involve some discussion with the FDA.  Suicidal ideation and behavior data derived from a trial 
348  in which suicidal ideation and behavior assessments were added after the trial was well along 
349  would not be optimal for inclusion in a meta-analysis.  It should be noted, however, that there is 
350  a version of the C-SSRS that is specifically designed for already-enrolled patients.  Whether or  
351  not such data will be useful in a meta-analysis, it may still be important to add suicidal ideation 
352  and behavior assessments for the protection of patients involved in the ongoing trial.  For a trial 
353  that is well along, it would not be feasible to go through the formal process of amending the 
354  protocol and obtaining investigational review board concurrence.  Nevertheless, even in these 
355  instances, it may be useful to alert investigative sites of the general concern about possible drug-
356  induced suicidal ideation and behavior, so they can individually decide how to address this issue.   
357   
358  6.  Prospective Assessments  in Large Simple Trials 
359   
360  The question has been raised as to whether prospective assessments for suicidal ideation and 
361  behavior would be needed in certain trials (e.g., a large simple phase 4 trial for which data 
362  collection is minimized).  An instrument such as the C-SSRS adds little burden to such a trial, as  
363  long as visit frequency is not altered, and increasingly these types of assessments are becoming 
364  part of clinical practice. Nevertheless, sponsors who have questions about what might be needed 
365  in a particular trial should ask the relevant review division about this.   
366   
367   
368  IV.  PROSPECTIVE ASSESSMENT OF SUICIDAL IDEATION AND BEHAVIOR  
369  OCCURRENCE  SPECIFIC INDICATION RECOMMENDATIONS  
370   
371  Past experience specifically indicates that assessment of suicidal ideation and behavior should be 
372  a regular part of development programs involving antidepressants and antiepileptic drugs.  But 
373  the heightened risk of suicide in most psychiatric illnesses strongly suggests that suicidal 
374  ideation and behavior should be assessed as part of the evaluation of any drug being developed 
375  for a psychiatric condition (i.e., those indications managed in the Division of Psychiatry 
376  Products). There are no data to support the view that patients with nondepressed psychiatric 
377  disorders have any lesser vulnerability to treatment-induced suicidal ideation and behavior than 
378  patients with overt depression. On the contrary, based on limited exploratory analyses of the 
379  trials using antidepressants in adults, including many trials in psychiatric patients with disorders 
380  other than depression, there is some evidence that the relative risk may actually be greater in 
381  nondepressed psychiatric patients (Stone, Laughren, et al. 2009).  Moreover, in the meta-analysis 
382  for suicidal ideation and behavior with antiepileptic drugs, the odds ratio for suicidal ideation 
383  and behavior was greater for epilepsy patients than it was for the psychiatric patients treated with 
384  these drugs, even though the absolute rates were higher in psychiatric patients compared to 
385  epilepsy patients.9    
386   
                                                 
9 See the Suicidal Behavior and Ideation and Antiepileptic  Drugs FDA Web page at  
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM100190.  
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387  Therefore, other than the exceptions noted in section III.C., prospective suicidal ideation and 
388  behavior assessments should be carried out in all clinical trials involving any drug being 
389  developed for any psychiatric indication, as well as for all antiepileptic drugs and other 
390  neurologic drugs with central nervous system (CNS) activity, both inpatient and outpatient, 
391  including multiple-dose phase 1 trials involving healthy volunteers.  Questions about what 
392  constitutes CNS activity should be addressed to the Division of Neurology Products.   
393   
394  Tempting as it may be to think that patients without a psychiatric condition receiving 
395  nonpsychiatric drugs would not be at risk for drug-induced suicidal ideation and behavior, 
396  experience suggests that this belief may be erroneous.  Although there are few controlled trial 
397  data in these settings, there has been long-standing concern about a variety of drugs, including 
398  isotretinoin and other tretinoins, beta blockers (especially those entering the brain), reserpine, 
399  drugs for smoking cessation, and drugs for weight loss, for which possible signals of risk for 
400  suicidal ideation and behavior have already been identified.  Therefore, at a minimum, we 
401  recommend that prospective suicidal ideation and behavior assessments be carried out in all 
402  clinical trials for all drugs that are pharmacologically similar to drugs in the above list.  These 
403  assessments, however, might reasonably be used more broadly, perhaps with any drug that 
404  appears to have a CNS effect. Sponsors are encouraged to contact the relevant review division to 
405  discuss whether these assessments are recommended for an individual drug.   
406   
407  Assessments should be conducted in both inpatient and outpatient trials, and even multiple-dose 
408  phase 1 trials involving healthy volunteers, with the exceptions noted in section III.C.  This list 
409  of suspect drugs will expand if new possible signals are detected, and it is plausible that certain 
410  drugs and pharmacologic profiles will prove not to be inducers of suicidal ideation and behavior.  
411  This cannot be known if the drugs are not studied.  One of the advantages of conducting suicidal 
412  ideation and behavior assessments more broadly is that future meta-analyses may either confirm  
413  the signal or provide reassurance that the signal is false.  The possibility that suicidal ideation 
414  and behavior assessments should be conducted as part of essentially all drug development 
415  programs, even for drugs not yet recognized as having CNS effects, has also been considered, 
416  but this guidance does not recommend that approach.  Further experience may change our view 
417  on this issue and comments on this current recommended approach are welcome.  Questions 
418  about whether a particular drug under development would need assessments for suicidal ideation 
419  and behavior should be directed to the review division that has responsibility for the indication in 
420  question. 
421   
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422  REFERENCES 
423   
424  Brent, DA, LL Greenhill, S Compton et al, 2009, The Treatment of Adolescent Suicide 
425  Attempters Study (TASA):  Predictors of Suicidal Events in an Open Trial, J. Am Acad Child 
426  Adolesc Psychiatry, 48:987-96. 
427   
428  Crosby, A, L Ortega, and C Melanson, 2011, Self-Directed Violence Surveillance:  Uniform  
429  Definitions and Recommended Data Elements, version 1.0, Atlanta (GA):  Centers for Disease 
430  Control and Prevention, National Center for Injury Prevention and Control. 
431   
432  Hammad, TA, T Laughren, and J Racoosin, 2006, Suicidality in Pediatric Patients Treated With 
433  Antidepressant Drugs, Arch Gen Psychiatry, 63:332-339. 
434   
435  Mundt, JC, JH Greist, M Federico, and K Posner, 2010a, Electronic Administration of the 
436  Columbia-Suicide Severity Rating Scale (eC-SSRS):  Results From 14,937 Administrations; 
437  from poster presented at ISCTM meeting, Oct 13, 2010, Baltimore. 
438   
439  Mundt, JC, JH Greist, AJ Gelenberg et al, 2010b, Feasibility and Validation of a Computer-
440  Automated Columbia-Suicide Severity Rating Scale Using Interactive Voice Response 
441  Technology, J Psychiatric Res, 44(16); 1224-1228. 
442   
443  Mundt, JC, K Posner, JH Greist, and M Federico, 2011, eC-SSRS Assessment of Lifetime 
444  Ideation and Behavior Are Predictive of Suicidal Behavior Occurring During Trial Participation;  
445  Poster presented at autumn meeting of ISCTM (Oct 3; Amelia Island, Fla). 
446   
447  Posner, K, GK Brown, B Stanley et al., 2011, The Columbia-Suicide Severity Rating Scale (C-
448  SSRS): Internal Validity and Internal Consistency Findings From Three Multi-Site Studies With 
449  Adolescents and Adults, Am J Psychiatry, 168:1266-1277. 
450   
451  Posner, K, MA Oquendo, M Gould, B Stanley, and M Davies, 2007, Columbia Classification 
452  Algorithm of Suicide Assessment (C-CASA):  Classification of Suicidal Events in the FDAs 
453  Pediatric Suicidal Risk Analysis of Antidepressants, Am J Psychiatry, 164:1035-1043. 
454   
455  Pumariega, A, U Millsaps, K Posner et al., 2011, C-SSRS:  Evidence-Based Method for 
456  Hospital-Based Suicide Screening; presented at Eastern Nursing Research Society 23rd Annual 
457  Scientific Sessions, Philadelphia, PA. 
458   
459  Stone, M, T Laughren, ML Jones, M Levenson, PC Holland, A Hughes, TA Hammad, R 
460  Temple, and G Rochester, 2009, Risk of Suicidality in Clinical Trials of Antidepressants in 
461  Adults: Analysis of Proprietary Data Submitted to U.S. Food and Drug Administration, BMJ, 
462  339:b2880. 
463   
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464  APPENDIX A: 
465  SUICIDAL IDEATION AND BEHAVIOR CATEGORIES AND  
466  DEFINITIONS (Posner, Oquendo, et al. 2007)10   
467   
468  Suicidal Ideation 
469   
470  Passive suicidal ideation: wish to be dead   
471   
472  Patient has thoughts about a wish to be dead or not alive anymore, or wish to fall asleep 
473  and not wake up. 
474   
475  Active suicidal ideation: nonspecific (no method, intent, or plan)  
476   
477  General nonspecific thoughts of wanting to end ones life or commit suicide (e.g., Ive 
478  thought about killing myself) without general thoughts of ways to kill oneself/associated 
479  methods, intent, or plan during the assessment period.    
480   
481  Active suicidal ideation: method, but no intent or plan  
482   
483  Patient has thoughts of suicide and has thought of at least one method during the 
484  assessment period.  This situation is different than a specific plan with time, place, or 
485  method details worked out (e.g., thought of method to kill self but not a specific plan).  
486  Includes person who would say, I thought about taking an overdose but I never made a 
487  specific plan as to when, where, or how I would actually do it . . . and I would never go 
488  through with it. 
489   
490  Active suicidal ideation: method and intent, but no plan  
491   
492  Active suicidal thoughts of killing oneself, and patient reports having some intent to act 
493  on such thoughts, as opposed to I have the thoughts but I definitely will not do anything 
494  about them.   
495   
496  Active suicidal ideation: method, intent, and plan    
497   
498  Thoughts of killing oneself with details of plan fully or partially worked out and patient 
499  has some intent to carry it out (i.e., some degree of intent is implicit in the concept of  
500  plan). 
501   
502  Suicidal Behavior 
503   
504  Completed suicide 
505   
506  A self-injurious behavior that resulted in fatality and was associated with at least some  
507  intent to die as a result of the act.  Evidence that the individual intended to kill him- or 
                                                 
10 See http://www.cssrs.columbia.edu.  
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508  herself, at least to some degree, can be explicit or inferred from the behavior or 
509  circumstance.   
510   
511  Suicide attempt 
512   
513  A potentially self-injurious behavior, associated with at least some intent to die as a result 
514  of the act.  Evidence that the individual intended to kill him- or herself, at least to some  
515  degree, can be explicit or inferred from the behavior or circumstance.  A suicide attempt 
516  may or may not result in actual injury.   
517   
518  Interrupted suicide attempt 
519   
520  When the person is interrupted (by an outside circumstance) from  starting a potentially 
521  self-injurious act (if not for that, actual attempt would have occurred).    
522   
523  Aborted suicide attempt   
524   
525  When person begins to take steps toward making a suicide attempt, but stops before 
526  actually engaging in any self-destructive behavior.  Examples are similar to interrupted 
527  attempts, except that the individual stops before being stopped by something else.  
528   
529  Preparatory acts toward imminent suicidal behaviors   
530   
531  This category can include anything beyond a verbalization or thought, but it stops short 
532  of a suicide attempt, an interrupted suicide attempt, or an aborted suicide attempt.  This 
533  might include behaviors related to assembling a specific method (e.g., buying pills, 
534  purchasing a gun) or preparing for ones death by suicide (e.g., giving things away, 
535  writing a suicide note). 
536   
537  Self-Injurious Behavior Without Suicidal Intent  
538   
539  Self-injurious behavior associated with no intent to die. The behavior is intended purely for 
540  other reasons, either to relieve distress (often referred to as self-mutilation (e.g., superficial cuts 
541  or scratches, hitting or banging, or burns)) or to effect change in others or the environment. 
542   
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