Adverse Event Summaries

There are myriad ways in which adverse event data can be summarized. Adverse events are summarized by overall occurrence, by maximum severity, and by maximum 

The following is a table specification, or table shell, for the summary of adverse events by body system, preferred term, and maximum severity. As a rule for this summary, a patient should be counted only once at maximum severity within each subgrouping. Denominators should be calculated as the sum of all patients who had the given treatment in the demographics file. 

By Body System, Preferred Term, and Greatest Severity 

Body System Preferred Term Active (N=x) Placebo (N=x) Overall (N=x)  

The following example relies on DATA step programming, a few SAS macro variables, and a final DATA NULL step with PUT statements for custom table presentation. Here are the adverse event summary annotated SAS program, notes for the program, and the output. 

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There are three problems with this adverse events summary. First, HEADACHE and HEDACHE are counted as separate events even though it is clear that the latter is simply a misspelling of the former. Second, MI and MYOCARDIAL INFARCTION are considered as separate events even though the former is simply an abbreviation of the latter. Finally, LIGHTHEADEDNESS/FACIAL LACERATION refers to perhaps related but different adverse events that need to be counted separately. All three of these problems exist because the data were entered in free-text fashion. 

Note that by changing the aesev variable to the aerel variable throughout Program 5.4, you can easily change the previous adverse event summary to a summary of adverse events by maximum drug relatedness. Also, if you remove the maximum severity steps, you get a typical overall summary of adverse events by body system and preferred term. Since patient medical history data are also often coded with MedDRA, patient medical history data may be summarized much like an overall summary of adverse events. However, frequently medical histories are collected in a checklist/checkbox format so that using a coding dictionary is unnecessary. 

Adverse Event summaries for each study underway or completed, including safety reports and death and dropout reports... 

CFR 514.80 (b) 4 New non-clinical and clinical data Adverse events not previously reported Summary of increased adverse event frequency Minor supplementary changes... 

CFR - Part 312.33 discusses what is required for an Investigational New Drug (IND) application. Part 312.33 discusses the requirements for the annual reporting for the IND. This reporting requires you to create adverse event, death, and subject dropout summaries annually for any drug under an IND application. 

You can see the benefit of coding the adverse events in the resulting summary. The headaches and myocardial infarctions are grouped appropriately, and splitting lightheadedness and facial laceration into separate events leads to those data being summarized separately as well. 

The study termination form data may be used for efficacy or safety analysis purposes. With regard to safety, if patients discontinue a study medication earlier than patients on standard therapy or placebo, then that is important to know. For efficacy analyses, patients who withdraw due to a lack of efficacy or adverse event may be precluded from being considered a treatment responder or success. Also, often the study termination date is used as a censor date in time-to-event analyses for therapy efficacy. Study termination forms play a key role in patient disposition summaries found at the start of a clinical study report. From a CDISC perspective, the study termination form is a finding. 

Medical dictionaries often need to be referenced when creating various analysis data sets For instance, perhaps the raw adverse event database in your clinical data management system contains only the MedDRA code. The code is worth having, but you would need the adverse event body system and preferred medical term to provide a useful summary of events. 

Safety results tables, which contain adverse event, laboratory, and vital signs data summaries. 

Program 5.4 Summary of Adverse Events by Maximum Severity... 

Since then there have been many publications and reviews of the UK yellow card system and spontaneous reporting systems internationally.A summary of the capabilities and limitations of the method is given in Table 15.6. Although these have been discussed in the greatest detail over the past three decades, the obligations that exist for pharmaceutical companies in the reporting of adverse events to the regulatory authorities at both national and international levels make it essential to review them in this chapter. 

Geriatric Considerations - Summary Use with caution due to the higher risk of GI and CNS adverse events. Not a preferred NSAID in older adulfs. Use of NSAIDs in older adulfs increases the risk of GI complicafions including gasfric ulcerafion, bleeding, and perforation. These complications are not necessarily preceded by less severe GI... 

JMP. An introduction to JMP teaches reviewers how to use JMP to review electronic data. Users learn how to use a variety of JMP functions to analyze electronic data, with a specific focus on adverse event, laboratory, exposure, and efficacy data. Basic functions of summary tables, graphs, statistical tests, and the formula calculator are covered. The course is taught in the computer lab with hands-on instruction. Prior completion of the NEDAT course or familiarity with electronic data sets or both are recommended. Although primarily geared toward the clinical reviewer, the course provides useful instruction for reviewers of all disciplines. 

Letter includes summary of action to date, planned action, and summary of any adverse events or outcomes... 

Provides update on all activities since last Annual Report, provides plans for future activities, and provides summary of any adverse events... 

Several summary tables are commonly presented to report safety data. Two examples of typical formats are provided here. Table 10.3 shows the format for the overall summary of adverse events falling within several adverse event categories. Such table shells are typically prepared by medical writers in advance of the study results being available and are based on the clinical study protocol and/or the statistical analysis plan written before the study started. Preparation in advance of the availability of the data saves time during the preparation of the clinical study report once the data are available. 

Safety information should be presented as a summary of adverse experiences by frequency and body system, except for patients who died or who left the study prematurely because of an adverse event. These should be described in detail, and the role of the drug should be evaluated for each reaction. The safety analysis should consider abnormal laboratory values as well as adverse experiences, and the following points should be kept in mind ... 

The adverse event section of the integrated summary of safety is divided into four sections as provided in the following outline. 

As implied by its title, the safety update report is not submitted with the original BLA, but is submitted in the form of updates at specific points in the application review process. Applicants must submit safety update reports 4 months after the BLA submission, after receipt of a complete response letter, and other times requested by CBER. In these reports, the sponsor must update the pending BLA with new safety information learned about the product that may reasonably affect the labeling statements in the contraindications, warnings, precautions, and adverse reactions sections. The updates must include the same types of information from clinical studies, animal studies, and other sources, and must be submitted in the same format as the BLA s integrated safety summary. They must also include case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event. 

Detailed summaries of safety data (clinical signs and symptoms, adverse events, and clinical laboratory values)... 

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