Adverse events severity

In guidance document ICH E3, Structure and Content of Clinical Study Reports, the FDA defines treatment-emergent signs and symptoms (TESS) as events not seen at baseline and events that worsened even if present at baseline. As simple as that may sound, it can sometimes be quite difficult to program. The important data variables that come into play are dosing record dates and times, adverse event start and stop times, and adverse event severity. All of these data variables need to be completed accurately for TESS to be calculated properly. 

In a randomized study in 956 volunteers aged 17-72 years a shortened immunization schedule of injections at 0, 1, and 2 months were compared with a schedule of injections at 0,1, and 12 months (16). Adverse events were transient and mild to moderate. Soreness was the most frequently reported local symptom (82%), whereas fatigue (20-22%) was the most frequently reported general symptom. Two volunteers had more serious adverse events severe chills and shaking in one and an episode of syncope (lasting a few minutes with complete recovery) on the day of the first dose in another. The authors concluded that doses at 0, 1, and 2 months would provide protection during a typical tick-transmission season. 

K. G. Kowalski, L. McFadyen, M. M. Hntmatcher, B. Frame, and R. Miller, A two part model for longitndinal adverse event severity data. J Pharmacokinet Biopharm 30 315-336 (2003). 

Six male healthy volunteers (mean age 31.5 years) received a single 45-mg oral dose containing 100 gCi [ C] dacomi-tinib. There were no serious adverse events, severe adverse events, or deaths during the study. In addition, there were no temporary discontinuations due to adverse events, and none of the subjects discontinued the study due to an adverse event. Mild adverse events were reported by two healthy volunteers dermatitis acneiform occurred in both subjects at approximately 100 h postdose, while dizziness, insomnia and photophobia occurred in one subject [60 ]. 

Cardiovascular Heart Only one subject had a serious adverse event (severe endocarditis after 15 days of treatment) [39]. 

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

Thiopurine S methyltransferase Low activity in about 10% of Caucasians and deficient activity in about 0.4%. High incidence of severe adverse events from azathioprine and 6-mercaptopurine in carriers of low activity. 

Miotto and colleagues (2001) surveyed 42 recreational users of GHB and found that 66% reported episodes of unpredictable loss of consciousness and 26% had overdosed. Forty-five percent of daily users had experienced frequent amnesia during or after use of the drug, suggestive of blackouts typically attributed to severe alcohol abuse. The rate of adverse events was greater... 

Adverse events need to be coded consistently with respect to letter case. Problems can occur when there is discordant coding using all capital letters, all lower-case letters, or combinations thereof, as computer software will interpret these capitalization variations as different events. Letter case sensitivity can be important when two or more words are used to describe an adverse event. For example, some databases utilizing the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary employ a coding system in which only the first letter of the first word of an adverse event is capitalized (e.g., Atrioventricular block complete ). Failing to adhere to uniform letter case conventions across the data can result in severe errors in data analysis. 

In postmarketing electronic longitudinal medical records, redundant and potentially contradictory information may come from several sources, (e.g., reports from medical residents, their supervisors, the attending physicians). In these cases time stamping of each event may help to delineate the important sequences in understanding the adverse events. 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

Figure 27.2 A display that summarizes the duration of treatment (black sqnares) and the timing of serious vascular events (circles) for the subset of patients who withdrew from treatment because of an adverse event. Each line represents a single patient s experience over time in days for the test (left panel) and the control drug (right panel). Patients are sorted by decreased duration of treatment. In this 1 1 randomized clinical trial there were 18 withdrawals due to a severe vascular adverse event with the test drug. This is in contrast with the control drug, with 11 withdrawals. Withdrawals with the test drug occurred sooner than with the control drug.

Regrettably, all chemotherapeutic agents have the potential to produce adverse reactions with varying degrees of frequency and severity, and these include hypersensitivity reactions and toxic effects. These may be dose-related and predictable in a patient with a history of hypersensitivity or a previous toxic reaction to a drug or its chemical analogues. However, many adverse events are idiosyncratic and therefore unpredictable. 

CrCl greater than or equal to 30 to less than 50 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment respectively. Renal function monitoring is recommended prior to initiation and periodically thereafter. Adverse events in clinical trials included nasopharyngitis (5.2%), upper respiratory tract infection (6.3%), and headache (5.1%). Currently, no significant drug interactions are known. 

Elicit adverse events of therapy in a non-leading manner and ask the patient to judge their severity. Ask the patient or par-ents/guardians what measures if any were used to ameliorate them. Assess adherence (ask patient or parents/guardians about missed doses do pill counts if the prescription vial is available). 

Dizziness, vertigo, nausea, vomiting, constipation, and lethargy are all relatively common adverse events. These effects are more pronounced for several days after initiation and following upward dose titration. Seizures have been reported rarely the risk is dose-related and appears to increase with concomitant use of antidepressants, such as tricyclic antidepressants or selective serotonin reuptake inhibitors. Tramadol should be avoided in patients receiving monoamine oxidase (MAO) inhibitors because tramadol inhibits the uptake of norepinephrine and serotonin. 

Adverse Event Start Date End Date Check If Ongoing Severity Action Taken Drug Relation Check If Serious... 

The adverse event form is a cornerstone of patient safety monitoring, and as such it contains very important data. There are several data issues for the statistical programmer to be concerned about here. 

Just as there is an adverse event form, there is usually a serious adverse event (SAE) form. Note here that serious as defined by the FDA is different from severe on the adverse event form. A patient can have a severe headache that may not be considered serious. The ICH guideline (also in ICH E3) entitled Clinical Safety Data Management Definitions and Standards for Expedited Reporting defines serious adverse events as follows ... 

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. 

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

KEEP ONLY LAST RECORD PER SUBJECT AT HIGHEST SEVERITY AS WE ONLY WANT TO COUNT A PATIENT ONCE AT MAX SEVERITY IF THEY HAD ANY ADVERSE EVENTS. data bysev set bysev ... 

By Body System, Table 5.4 Adverse Events Preferred Term, and Greatest Severity ... 

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