In the last issue, I stated that a more accurate definition of Screening Failures may be as following “Potential subjects who were screened for the study participation, but were not enrolled (randomized or dosed) for the study”
Once we know the definition of the screening failures, the next question is about the data collection for screening subjects in clinical trials. How much data should we collect for screening failures? Should AE be collected and entered into the clinical database? for screening failures, should SAE be reported to regulatory agency and should SAE narratives be written?
Let’s take a look at a web posting of question and answers about the AE collection for screening failures below:
Question:
I have a question related to the collecting and recording of screening failure adverse events during clinical trials. I work for a data management group of a medium sized pharma company. Currently we collect and database all AEs that occur to screening failures in our clinical trials.
On further research I have not been able to find any regulation or guidance document that requires this. Can you tell me what the FDA position is on this?
Should we
1) Record and database all AEs for screening failures?
2) Not record and database AEs for screening failures?
Clinical Site Quality Control
3) Not record or database and put systems in place that can detect an unusually large number of AEs in a specific site for screening failures.
Answer:
I'm not sure what you mean by "screening failure adverse events." Are you referring to an intercurrent illness or condition that occurs between the time that the subject was enrolled but before randomization that leads to the subject being considered a screening failure? If so, we do not consider these to be adverse events; because the subject has not yet received any study drug, it would not be "associated" with the use of the test article. Nevertheless, because the intercurrent illness or condition affects the subject's eligibility for the study, it should still be recorded by the study site and reported to the sponsor. The clinical investigator should also ensure that the subject receives appropriate medical care, either by providing it directly or by referring the subject back to the subject's primary care physician.
The answer above was not all accurate. During the screening period, subjects were exposed to the screening procedures which could cause adverse events; subjects could have emotional changes / nervousness / anxiety just because of the study participation; subjects could be asked to change their regular treatment/medication to meet the inclusion / exclusion criteria that in turn could cause side effects (such as withdrawal effect). Therefore, it is very possible for subjects to develop adverse events during the screening period. In other words, adverse events can be reported for screening failure subjects even though the subject has not yet received any study drug. Question:
I have a question related to the collecting and recording of screening failure adverse events during clinical trials. I work for a data management group of a medium sized pharma company. Currently we collect and database all AEs that occur to screening failures in our clinical trials.On further research I have not been able to find any regulation or guidance document that requires this. Can you tell me what the FDA position is on this?
Should we
1) Record and database all AEs for screening failures?
2) Not record and database AEs for screening failures?
Clinical Site Quality Control
3) Not record or database and put systems in place that can detect an unusually large number of AEs in a specific site for screening failures.
Answer:
I'm not sure what you mean by "screening failure adverse events." Are you referring to an intercurrent illness or condition that occurs between the time that the subject was enrolled but before randomization that leads to the subject being considered a screening failure? If so, we do not consider these to be adverse events; because the subject has not yet received any study drug, it would not be "associated" with the use of the test article. Nevertheless, because the intercurrent illness or condition affects the subject's eligibility for the study, it should still be recorded by the study site and reported to the sponsor. The clinical investigator should also ensure that the subject receives appropriate medical care, either by providing it directly or by referring the subject back to the subject's primary care physician.Different situations for adverse event collections can be listed in the table blow:
All Subjects Screened
| ||
Eligible for study participation
|
Screening failures
| |
| Adverse events during the screening period starting from ICF signing |
Non treatment-emergent adverse events
|
Non treatment emergent adverse events
|
| Adverse events reported after the first dose of the study drug |
Treatment-emergent adverse events
|
-
|
| Statistical analysis |
Non-treatment emergent and treatment emergent adverse events are summarized separately
|
Not included in statistical analysis since screening failures are not included in safety population
|
From the table above, we can see the followings:
1. For subjects who are eventually randomized and receive the study medication, all adverse events need to be captured and recorded in the clinical database starting from the informed consent signing. By comparing the AE onset date/time with the first dose date/time, the AEs can be separated as non-treatment emergent AEs and treatment emergent AEs.
For this group of subjects, it is accurate to say that any AE occurred after the informed consent signing should be recorded.
2. For screening failures, whether or not the AEs reported during the screening period should be recorded in the clinical database is up for debating.
- Some companies do not record any data into the clinical database for screening failures. All information about the screening failures are maintained in a screening log.
- Some companies record only the key information into the clinical database for screening failures. The key information may be demographics, reason for screening failures
- Some companies choose extreme conservative way and record all available information for screening failures in the clinical database.
Unfortunately, there is no clear regulatory guidance on what information (especially adverse events) should be recorded into the clinical database for screening failures. The languages from In ICH E3 (STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS), seems to suggest that for screening failures, only information needed may be the reason for screening failures (and adverse event could be one of the reasons for screening failure).
The most extreme (or conservative) situation could be that in a study, the SAE narratives would be written for all subjects including the screening failures. In order to have sufficient information for SAE narrative writing for screening failures, all details about SAE and the ancillary information (physical example, medical history, vital signs, laboratory, …) would need to be collected. A lot of time and efforts would be spent on the data collection, but the collected data would not be very useful or at least not relevant to the purpose of the study since in the end, the screening failures would be excluded from the safety population for the safety analysis. This practice of collecting almost every detail about the screening failures is not wrong, but is not an efficient way for conducting the clinical trials.
Nowadays, the industry trend is moving toward to being compliant with CDISC standards (SDTM, aDaM). There seems to be a lot of confusions about whether or not data for screening failures should be included in the database and if so, where to include. The following weblinks from CDISC Public Discussion Forum show the confusions.
To summarize, for screening failures, the best way for data collection may be to collect only the demographic information and the reason for screening failures in clinical database. The reason for screening failure should include a category of “AE” since subject can be screening failure due to AE (or precisely non-treatment emergent AE) during the screening period. The details about the AE / SAEs for screen failure subjects are not necessary to be entered into the clinical database.
