Electronic data capture and Eclinical trials

e-trials accepted

Electronic common technical document by ICH Electronic records, electronic signature regulation-21CRF part 11 Electronic Source Documentation in Clinical Investigations- guidelines by FDA dec 2010

Clinical data interchange standard consortium standards accepted by FDA FDA republished guidelines for computerized systems used in CT-2007

E-clinical trial
Clinical Data Interchange Standards Consortium (CDISC) defines an electronic clinical trial (eCT) as:Clinical trial in which primarily electronic processes are used to plan, collect, access, exchange and archive data required for conduct, management, analysis and reporting of the trial (CDISC, 2006). Over the past fifteen to twenty years, many different forms of site-based capture of clinical trial data have been developed. Data collection technology that has been applied to improve clinical trial data collection is generally referred to as electronic data capture (EDC) (Kush et al., 2003)

Additional requirements

Maintenance of technical systems Software upgrade Integration of protocol amendments into EDC

24/7 help desk

Benefits of electronic data collection

Reduces data transmittal time to the sponsor or CRO Eliminate the step of having data doubleentered. Better data quality Improved performance Reduced cost

Guttman scale for defining functionality levels for an EDC

Early focal points for e-based approach in conduct of trials

Monitoring Adverse event reporting Data collection

Investigator identification

Database of investigators Investigators past performances Uses vendors / internal databse

Finding and enrolling patients:

e-recruiters Web based sites

www.clinicaltrials.gov

www.centerwatch.com

Medication dispensing and automated site inventory control using Interactive Voice Response

Assembly and processing of data elements using the eCRF as a platform

Data entry

Data review

Data processing and transmission

Web Based Data Capture for Clinical Research

all users of the Data Collection tool must logon with a unique username and password After logging on, the user will see a list of trials that have been defined for the users sponsor

A Diabetes center

After selecting the study by clicking on the hyperlink, the list of sites for that study appears

After selecting the site to be worked on, a list of patients is displayed

Whether a new patient is created or an existing patient is reopened, the patients trial hierarchy will be displayed

As the Date of Exam and Systolic fields have been set up with a Required edit check through the Study Build tool, submitting the form without any further data entry would result in the form being repainted with the following discrepancy text in red

Edit checks

date check that was set up on the Date of Birth field appears on the Demographics forms.

Example of Data Elements and Data Element Identifiers

Example of Modification/Correction

Example of List of Authorized Data Originators

Direct data entry into computers

ECG and PFT to study database

Tablet PC Palm handheld units

Electronic Patient Reported Outcomes (ePROs)

Easy-to-use by Subjects Attributable, Time-Stamped Data for Rapid Analysis Increased Efficiencies for Sponsors and CROs Ensures Protocol Compliance Improved Clinical Care during the Trial FDA guidelines relating to EDC system provides a framework to use for collecting these data. Comparison of compliance with paper diaries. ( BMJ stone et al.2002)

Regulating EDC
Procedural control: Trial organization and documentation Technical control: To ensure quality, accuracy and integrity of data stored User authorization control Audit trial control Attributability control Data validity control System integrity measures.

Auditing Electronic data capture in clinical trials

Where do auditors see EDC Systems?
During CRO-Audits EDC-Systems, which support the study conduct and are used for documentation of data. During investigational site audits special systems for data entry are evaluated.

Regulatory basic documents

Electronic Records, Electronic Signatures 21 CFR part 11 March 1997 Annex11 to GMP guide: Supplementary guidelines for computerized systems 1992 Guidance for Industry, Computerized Systems used in Clinical trials April 1999.

Key requirements

Computer /EDC-Systems
-unlimited access for the whole personnel of a hospital / outpatient clinic - deficient data security - missing SOPs and documented training - inadequate or missing validation of programs

Findings due to technical issues

Patient data and measured values can be entered repeatedly. Previous data are altered or deleted without recording in an audit trail. On paper printouts the print date in stead of the measurement date is printed. Saving of entered data was not automated leading to loss of data. Data are not adequately secured on the hard disc, e.g. no re-write protection. Manipulation possible. During transfer of laboratory data, units are changed without previous co-ordination, warning or notification. While the monitor was logged in to the system the investigator couldnt work. Data transfer from the investigator to the host of the system wasnt possible several days. Potential for data loss.

Implementation of study protocol in to the EDC-System

The parallel work on related CRF-pages was not possible. User unfriendly navigation in the e-CRF leads potentially to higher error rate (motivation decreases). Data were deleted by the system during review process. Computer accepts no calibrated data e.g. from lab devices. Pre-defined data checks are not carried out.

Related mistakes following cumbersome data documentation

Data were initially documented on paperprint outs. Paper hospital chart, paper-CRF and e-CRF are available. This leads to inconsistencies, more work for the physician, increase of error rate, increase in paper load. Manual entry of data by an investigator e.g. from patient diaries leads to increased error rates (the investigator is not a trained datatypist).

Steps to improve data management in the e-process

Company endorsement Site endorsement Training Redefine or refine the data management process. Integration of paper CRFs and EDC is often a desirable approach.

Archival Requirements
Electronic records must be archived in electronic form. The electronic records must be protected to enable their accurate and ready retrieval throughout the relevant retention period. Keep accurate transcriptions or complete copies of data and metadata on durable media Keep links between e-signature and electronic document Tighter controls may be required for opensystems (encryption & digital sigs)

Evaluation of vendors
Experience with the pharmaceutical industry and clinical trials Technical knowledge Financial status Knowledge of the investigators clinical environment and how the information needs to flow. Ability to include redundancy to overcome equipment or power outrages at the time of patient visit.

Increasing success of e-trials

Technical personnel to assist staff. Working together as a team Technical support to patients. SOP for EDC and e-clinical trials. Project manager to be conversant with procedures and requirements. Gradual building of EDC Training / monitoring performance

Advantages and disadvantages of using the internet to conduct clinical trial

Topic Communication Feasibility Advantages Less expensive, faster, & easier Online clinical trial system is easier and less expensive to scale to multiple sites across multiple countries. Online training is easily accessible Broadcast medium to advertise real time view of newly registered patients Eliminate the need and expense of 24 hour call in center. Concealment of allocation is easier. Disadvantage are they Secure ? Selection bias

Training Recruitment

May not be as effective as alive educator. Security of online data Technical difficulty reduces recruitment Hard to locate computer terminal than a telephone at the patient contact.

Randomization

cont.
Data collection Real time data validation Increases quality and speed of data acquisition No double-keyed data entry Monitors have real time access to all aspects of the trial IRB have real time access to adverse events Input is slowed at peak internet use when access to web server is slowed. Less in person monitoring increases problems to be identified.

Monitoring

Safety

Security

Sensitive patient data is centralized in one location

Reduced

Online data can be intercepted during transmission.

Experienced computer professionals required Not feasible for smaller trials Duplicate internet pages in multiple languages No guarantee for 3rd party internet resources

Study personnel

Administration paper reporting Central updation of protocol and CRF Audit trail Online clinical trial system could be used for multiple trials

The CRF should be designed to capture all data required per the study protocol, (2) the CRF should be designed to collect data elements in standardized format, (3) data elements should be captured on the CRF in a fashion that ensures that data are suitable for summarization and analysis, (4) data elements planned to be transcribed to the CRF from source documents should be organized and formatted on the CRF to reduce the possibility of transcription error and to facilitate subsequent comparison to source documents, (5) ease of completion for the investigator and study coordinator is key to accurate and timely CRF completion, and (6) redundant data elements within the CRF should be avoided and unnecessary data should not be collected. It is essential that all and only the necessary data be collected. CRF should be designed in a way that promotes simple database design, data capturing, and data validation. A typical approach for development of CRF is the so-called backwards approach. The backwards approach to CRF design starts with assessing the type and format in which information will be presented in the study report. Information is then tracked backwards, and the CRF is designed to capture data in a manner that allows them to be easily converted or directly placed in the designed tables or figures

Completing a CRF

The eCRF is a vehicle used to assemble all the data from different electronic- and paper-based systems and makes it possible to capture and organize these diverse data in a manner that satisfies the study protocol and that enables the data to be systematically reviewed and analyzed by investigators, other authorized parties, and FDA

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Regulators