Seeing Chickens at Window Recording Adverse Events and GeneratingQuality Data Margaret Band, Clinical Trial Manager, TCTU
Adverse Event Reporting Monitoring of adverse events (AEs) is critical to the patient s safety and data integrity & a legal requirement The Medicines for Human Use (Clinical Trials) Regulations 2004
Introduction Definition of AEs Purpose of recording AEs Documenting AEs Completing and AE form description, severity, causality and outcome Reporting AEs briefly! AE SOP
Definition of Adverse Events AE - Adverse Event Any untoward medical occurrence or the deterioration of a preexisting medical condition in a subject in a clinical trial An AE does not necessarily have to have a causal relationship with the study treatment / procedure An AE can therefore be any unfavourable and unintended sign (eg. tachycardia) including laboratory findings which are clinically significant, symptom (eg. nausea, chest pain) or a disease The term AE is used to include both serious and non-serious AEs Elective hospitalisations for pre-treatment conditions are not AEs
Definition of Adverse Events AR - Adverse Reaction An adverse reaction (AR) is where it is suspected that an AE has been caused by a reaction to a trial drug The reaction may be a known side effect of the medication (AR) or it may be a new previously unrecognized adverse reaction (UAR) UAR - Unexpected Adverse Reaction An AR wich is not described in Investigator s Brochure (IB) or Summery of Product Characteristics (SmPC) Not all AEs are ARs but all ARs are AEs
Serious Adverse Events All SAEs are AEs not all AEs are SAEs Usually any AE, AR or UAR that at any dose: results in death; is life threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe); requires hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect. is considered a SAE. However
Serious Adverse Events The reporting of SAEs can be excluded if documented in the study protocol. The exclusion of reporting some SAEs may be due to their expected occurrence in the population and disease under investigation These should be recorded in the AE log but no SAE form required.
Purpose of recording Adverse Events Legal requirement - The Medicines for Human Use (Clinical Trials) Regulations 2004 Safety Signals Informs Data Monitoring Committee safeguard the interests of trial participants assess the safety and efficacy of the interventions during the trial monitor the overall conduct of the clinical trial Accuracy in diagnosis is important for detection and evaluation of safety signals
Purpose of recording Adverse Events Regulatory authorities want to see if a drug trial follows reported side effect profiles as reported in the Investigators Brochure and Summary of Product Characteristics New drugs have to build up this profile in clinical trials AE analysis must count side effects for each treatment arm Companies must keep track of the side effect profile of their drugs
Coding of Clinical Trial Data Most data entered on Case Report Forms are coded in some form Some coding is performed by investigators at point of data entry For example, numeric codes for severity of adverse event: 1= mild, 2= moderate, etc. Coding of free text data, as provided in an AE Log, is performed after data collection, free text is otherwise not analyzable Coding AEs allows free text to be grouped into meaningful categories for analysis to quantify AEs for a particular study Most research organisations will use a specific coding mechanism to ensure consistency of coding TCTU uses MedDRA - Medical Dictionary for Regulatory Activities Accuracy of coding determines accuracy of analysis
Coding Challenges Some reported AEs! Not from TCTU! Went to hell Recurrent fatal stroke Hears New Age music when the furnace turns on LK RTCTL UNSP XTRNDL Charcoal-like, gritty granules in his underwear Can t control patient during menses His nodule is sticking out Normally normal after drinking coffee Died of cancer of the placebo Superior members fornication Barely visible posterior Seeing people in room, seeing chickens at window Seeing stars and chicken farting Patient recently began new job where he works around chicken wings and barbecue sauce
Documenting Adverse Events AE log Medical notes
Includes: Date of onset Description Severity Causality Action Outcome End date The Adverse Event Log
Adverse Event Log
Date of Onset Date event started not date first reported to investigator.
Description of AE Benefits of Quality Data Generating Quality Data Coding of Clinical Trial Data Symptom vs Syndrome Problems with Coding Data
Benefits of Quality Data Accurate and timely information on issues that affect conduct of clinical trial and affect patient safety Improved communication among sponsors, investigators, and regulatory agencies about medicinal products Aids in safety signal detection and evaluation Ensures accuracy of information about the product including investigators brochures and prescribing information Benefits medical professionals Benefits patients
Generating Quality Data Clear Concise Complete Accurate Be specific if possible - Headache - more than 50 types, including cluster, sinus, migraine, lumbar puncture headache Organisms - down to species level e.g. Staphylococcus aureus
Symptom vs Diagnosis Where possible, report the most important medical event or specific diagnosis rather than individual signs and symptoms Can provide provisional diagnosis e.g. possible, presumed, rule out Diagnosis should not be assumed by Research Nurse Accuracy is important in preventing dilution of safety signals or generating Signs and symptoms false signals chest pain, breathlessness, sweating, ECG changes Diagnosis Myocardial infarction E.g. Report AE as Myocardial Infarction
Problems with coding data Appropriate coding requires clear initial data What is clear to the investigator at the point of data entry may be unclear to the coder at the point of data coding Sponsor must only code reported verbatim term; not permitted to interpret or draw information from other sources
Generating Quality Data Avoid: Ambiguous information Congestion (nasal, liver, sinus, pulmonary?) Cramp (muscle, menstrual, abdominal?) Pain (where?) Ambiguous abbreviations MI (myocardial infarction or mitral incompetence?) GU pain (gastric ulcer pain or genito-urinary pain?) Decreased BS (breath sounds, bowel sounds or blood sugar?) Exercise caution with abbreviations that could be misinterpreted Vague information Patient felt fuzzy, weird, experienced every adverse event
Generating Quality Data Try to use accepted medical terminology Give specific information Non-specific information Oedema (coded as oedema) Left wrist oedema (coded as Peripheral oedema) More specific - Injection site oedema left wrist (coded as Injection site oedema)
Generating Quality Data Death, hospitalization, investigations and disability are outcomes and are not usually considered to be adverse events Provide details of the underlying event, if known Examples: Death due to myocardial infarction (Coded as Myocardial infarction with death captured as the outcome) Hospitalization due to congestive heart failure (Coded as Congestive heart failure with hospitalization captured as the outcome)
Generating Quality Data Recording laboratory data Ambiguous laboratory data Glucose of 40 (Source of specimen - blood, urine, CSF? What units?) Would have to code as Glucose abnormal if additional clarification is not obtained Conflicting laboratory data Hyperkalemia with serum potassium of 1.6 meq/l Would have to code as Serum potassium abnormal If using numeric values, provide units and reference range. Be specific about specimen source and diagnostic result/clinical diagnosis.
Generating Quality Data Try to avoid combination terms - these will have to be split into individual terms Combination terms Diarrhoea, nausea and vomiting Should be recorded as: Diarrhoea Nausea Vomiting
Generating Quality Data Falls: a fall in it s self is not an AE however, If a patient hurts themselves record any injury as AE Fractured right wrist due to fall If an underlying cause is present record cause as AE Postural hypotension resulting in fall
Assessing severity MUST be assessed by medically qualified person on delegation log (legal requirement) Mild- awareness of sign or symptom, but easily tolerated Moderate- discomfort sufficient to cause interference with normal activities Severe- incapacitating with inability to perform normal activities Severe is not the same as serious!
Assessing Causality MUST be assessed by medically qualified person on delegation log (legal requirement) Unrelated - not considered to be related to study drug/intervention, other cause is more probable. Possibly although a relationship to study drug/intervention cannot be completely ruled out other explanations are more likely Probably - good reason and evidence for relationship to study drug/intervention and absence of a more likely explanation Definitely the known effects of the study drug/intervention or challenge testing suggest the study drug/intervention is the most likely cause.
Action taken Action to the study drug/intervention e.g. stopped, dose reduced Other medication started/stopped/dose change Other treatment required e.g. physio Hospitalisation Remember: if study drug/intervention stopped or reduced this should be recorded in the CRF any action to other medication, started/stopped/dose change, should also be recorded in the Concomitant Medications Log
Outcome Resolved date Ongoing - all AEs should be followed up to resolution or end of study Resolved with seaquelae disability or incapacity Death date
Up Dating AE Logs All AEs should be followed up until resolution or end of study Unless resolved every AE should be reviewed at each visit Assess if still ongoing or now resolved Assess if action taken has been changed Assess if diagnosis has been made/changed Correct AE if necessary E.g. Chest pain now been diagnosed as angina: change AE to angina (remember to sign and date changes on paper CRF and update OpenClinica/data management system) If several AEs now have one diagnosis change first AE to new diagnosis and score through additional AEs (update data management system) E.g. Separate AEs of diarrhoea and vomiting now diagnosed as Gastroenteritis : change diarrhoea to Gastroenteritis score through vomiting AE. The patient now has only one AE Gastroenteritis. At end of study ensure all AEs are either resolved (give end date) or ticked as ongoing (e.g new diagnosis of diabetes)
Up Dating AE Logs example
Medical Notes All AEs reported by the patient should be documented in the patient s medical notes If any action has been taken by the study team this should be recorded GP should be informed if it is felt necessary, ask the patient s permission Medical notes can be used as source data for AEs
Reporting AEs to Sponsor Complete CRF and enter in OpenClinica/data management system in timely manner Data used to inform Data Monitoring Committee
AE SOP TASC SOP 11: Identifying, Recording and Reporting Adverse Events for Clinical Trials of Investigational Medicinal Products http://www.tascresearch.org.uk/cms/files/sop11/sop_11_v_7.0.pdf