Topics Electronic diaries in Clinical Trials Electronic diaries versus Paper Electronic patient diaries in clinical research Case Study: Novel detection of exacerbations of COPD with patient reported outcome (EXACT-PRO) and Blackberry Isabella Montagna Annamaria Muraro Electronic diaries compliance with regulations Good Clinical Data Management Practices Case study: Forward, CHIESI Farmaceutici The EXACT-PRO questionnaire on BlackBerry Electronic data flow Electronic diaries improvement in study Detection of ECOPD with EXACT-PRO and BlackBerry Conclusions 2
Electronic diaries Electronic diaries Subjects diaries are essential in clinical trials that assess occurrence and intensity of symptoms, effects of medication, perceived quality of life. Scientific research has consistently demonstrated that paper diaries make difficult for subjects to comply with the protocol. Otherwise electronic diaries ensure undeniable advantages. By capturing data directly from patients at home, they solve problems often experienced by using paper diaries. What electronic diaries do (and paper diaries don t) Record date and time for each entry automatically Prevent to skip mandatory information Allow to enter only formatted responses Remind automatically to complete Transfer data directly to a central database Make real-time data available to all More pharmaceutical companies worldwide replace paper diaries with electronic ones. 3 4
Electronic diaries vs paper Electronic diaries vs paper Electronic diaries Pros Reliable, real time data Reduced missing data Reduced data entry errors High diaries compliance and possibility to monitor it Real time access to study and patient data Integration with clinical databases Cons Training required Familiarity with technology More startup resources needed Paper diaries Pros Established medium Fewer startup resources No training required Easy to produce Cons No reliable date/time stamping (retrospective data entry) Poor quality of data (incomplete, unreadable information, inappropriate responses) Lack of compliance 5 6
Electronic diaries compliance with regulations FDA draft Guidance for industry: Electronic Source documentation in Clinical Investigations (January 2011). EMA Expectations from Electronic Source Data and Data Transcribed To Electronic Data Collection Tools in Clinical Trials (September 2010). FDA Guidance for industry: Patient Reported Outcome measures: Use in in Medical Product Development to support Labeling Claims (December 2009). CDISC Leveraging the CDISC standard to facilitate the use of electronic source data within clinical trials (November 2006). US 21 CFR Part 11 Electronic records, electronic signatures (1997) Electronic Diaries - Good Clinical Data Management Practices Electronic diaries collect Patient Reported Outcome to quantify symptoms, disability, emotional states, responses to treatment, Questionnaires are often developed to measure PRO and to quantify the results by established algorithms. Best Practices for epro Use standard, validated questionnaires. Provide detailed instructions to subjects for completion of the electronic diary and conduct appropriate training. Ensure electronic systems are proper validated in compliance with US 21 CFR Part 11. Ensure all processes are in place to assure compliance with regulatory requirements regardind protection and ownership of electronic data. Ensure appropriare level of network security and infrastructure. 7 8
Case Study: Forward, CHIESI Farmaceutici Case Study: Forward, CHIESI Farmaceutici Forward is a Clinical Study sponsored by Chiesi Farmaceutici aimed at demonstrating that Foster, a drug registered to cure a severe respiratory pathology called asthma, can be also used to effectively cure another respiratory disease called Chronic Obstructive Pulmonary Disease (COPD). More than 1000 patients involved from 18 countries and treated for 48 weeks. The Clinical Study must satisfy all regulatory authorities and legislation requirements, reaching an effective symptoms control that can be obtained only with a day-by-day report from patients about their health status and frequent visits to the medical centres. To comply with protocol requirements, Chiesi Farmaceutici adopted the solution of electronic diaries. Blackberries were identified as the best technological platform to host the EXACT-PRO questionnaire. 9 10
The EXACT-PRO questionnaire The EXACT-PRO questionnaire The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) is a patient-reported outcome (PRO) measure designed to standardize the method for evaluating the frequency, severity, and duration of acute exacerbations of COPD and chronic bronchitis (AECB) in international studies and clinical trials. The EXACT is a 14-item daily diary to be completed by the patient on the device each evening before bedtime, taking less than 3 minutes to complete. Chiesi customized EXACT-PRO with 4 study specific additional questions. 14 questions Total score - 0 to 100 (higher scores = more severe health status) Domain scores - Scoring 0 to 100 (higher scores = more severe symptoms) - Breathlessness (5 Items) - Cough and Sputum (2 Items) - Chest Symptoms (3 Items) 4 custom questions to record information on rescue medication and study treatment intake. 11 12
EXACT-PRO on BlackBerry EXACT-PRO on BlackBerry The electronic diary on BlackBerry was given to each patient for recording: Daily symptoms and patient status Use of recue medication Compliance of study medication intake. The patients were instructed on how to use the device. Mean patients age: 64 years To facilitate patients in approaching technology, the following measurements were adopted: the clinical study application is the ONLY application to which the users have access only one question per page is displayed. To achieve compliance with the protocol, the following settings were applied: each question must be answered and edited by patients patients can edit today s diary only notifications remind patients to fill in the questionnaire. BlackBerry is one of the most user-friendly device. 13 14
EXACT-PRO on BlackBerry EXACT-PRO on BlackBerry To comply with privacy requirements: patients remain anonymous to Chiesi who only gets data about questionnaire tracking BlackBerry PIN communications are encrypted no data are stored on the device but information are immediately transmitted to the central database and synchronized in a secure Web portal. No need for telephone line (only mobile signal required). Patients health is always controlled by notifications automatically sent to patients and investigators. Notifications to the patients Global (automatically scheduled and delivered) Individual (in case of symptoms worsening) Please remember to call your doctor if your symptoms worsen. Notifications to the investigators Variation in patient s symptoms will trigger an alert that will be sent by e-mail or by text. 15 16
Electronic diaries data flow Electronic diaries compliance Subjects Diary Database Diary Web Portal BlackBerries compliance during treatment period EXACT-PRO ALERT Investigator ALERT 100.00 90.00 80.00 70.00 60.00 50.00 40.00 30.00 20.00 10.00 0.00 CHIESI Clinical database Compliance = total days recorded in the BB / total days expected * 100 Mean compliance = 88.64% 17 18
Detection of ECOPD with EXACT-PRO and BlackBerry Detection of ECOPD with EXACT-PRO and BlackBerry Electronic diaries but not only +12 pt Threshold Exacerbations of COPD are estimated from persistent increase in daily symptoms that require treatment with systemic steroids, antibiotics and/or hospitalization/er visit. CHIESI Farmaceutici employs electronic diaries on BlackBerry to automatically detect possible ECOPD. A baseline score is set in the device to identify the patient s stable condition. Baseline score = value calculated during the 14 days run-in period when patients are treated with their maintenance therapy. Baseline 1 event as per the EXACT-PRO detection definition Any variation in score of at least 12 points for two consecutives day is considered as significant worsening of the patient s status. 19 20
Detection of ECOPD with EXACT-PRO and BlackBerry Conclusions Electronic diaries improvement in studies More precise data as they are collected daily. Real-time data available both to investigators and sponsor. Daily monitoring of patients health. Daily monitoring of patients compliance in BlackBerry usage and in study medication intake. A - The EXACT-PRO detection threshold matches the diagnosed ECOPD. B - Patient s condition worsens according to symptoms recorded in the BB but no subsequent treatment until further worsening triggering treatment. C - No clear worsening recorded in the BB but patient receives treatment for ECOPD. Corrective actions immediately in place to correct lack of compliance: additional training to patient BlackBerry replacement in case of device malfunction. Savings in questionnaires collections (automatic data transfer to the clinical database) and analysis Savings in the visits with doctors. 21 22