Clinical data management

Clinical data management encompasses the entry, verification, validation and quality control of data gathered during the conduct of a clinical trial.

Role of the Clinical Data Manager in a Clinical Trial

The Clinical Data Manager plays a key role in the setup and conduct of a clinical trial. The data collected during a clinical trial will form the basis of subsequent safety and efficacy analysis which in turn drive decision making on product development in the pharmaceutical industry. The Clincal Data Manager will be involved in early discussions about data collection options and will then oversee development of data collection tools based on the clinical trial protocol. Once subject enrollment begins the Clinical Data Manager will ensure that data is collected, validated, complete and consistent. The Clinical Data Manager will liaise with other data providers (eg a central laboratory processing blood samples collected) and ensure that such data is transmitted securely and is consistent with other data collected in the clinical trial. At the completion of the clinical trial the Clinical Data Manager will ensure that all data expected to be captured has been accounted for and that all data management activities are complete. At this stage the data will be declared final (terminology varies but common descriptions are Database Lock and Database Freeze) and the Clinical Data Manager will transfer data for statistical analysis.

Standard Operating Procedures

Standard Operating Procedures (SOPs) describe the process to be followed in conducting data management activities and support the obligation to follow applicable laws and guidelines (eg ICH GCP and 21CFR Part 11) in the conduct of data management activities.

The Data Management Plan

The Data Management Plan will describe the activities to be conducted in the course of processing data. Key topics to cover will include the SOPs to be followed, Clincal Data Management System to be used, description of data sources, data handling processes, data transfer formats and process, and Quality Control procedures to be applied.

Case Report Form Design

The Case Report Form (CRF) is the data collection tool for the clinical trial and can be paper or electronic. Paper CRFs will be printed, often using No Carbon Required paper, and shipped to the investigative sites conducting the clinical trial for completion after which they are couriered back to Data Management. Electronic CRFs enable data to be typed directly into fields using a computer and transmitted electronically to Data Management. Design of CRFs needs to take into account the information required to be collected by the clinical trial protocol and intended to be included in statistical analysis. Where available, standard CRF pages may be re-used for collection of data which is common across most clinical trials eg subject demographics.

Database Design and Build

For a clinical trial utilising an electronic CRF the database design and build and CRF design are closely linked. The electronic CRF will enable entry of data into an underlying relational database. For a clinical trial utilising a paper CRF the relational database will be built separately. In both cases the relational database will allow entry of all data captured on the CRF.

Computer System Validation

All computer systems used in the processing and management of clinical trial data must undergo validation testing to ensure that they perform as intended and that results are reproducible.

CDISC

The Clinical Data Interchange Standards Consortium leads the development of global, system independent data standards which are now commonly used as the underlying data structures for clinical trial data. These describe parameters such as the name, length and format of each data field (variable) in the relational database.

Validation Rules

Validation rules are electronic checks defined in advance which ensure the completeness and consistency of the clinical trial data.

User Acceptance Testing

Once an electronic CRF is built the clinical data manager (and other parties as appropriate) will conduct User Acceptance Testing (UAT). The tester will enter data into the electronic CRF and record whether it functions as intended.

Data Entry

When an electronic CRF is in use data entry is carried out at the investigative site where the clinical trial is conducted by site staff who have been granted appropriate access to do so.

When using a paper CRF the pages are entered by data entry operators. Best practice is for a first pass data entry to be completed followed by a second pass or verification step by an independent operator. Any discrepancies between the first and second pass may be resolved such that the data entered is a true reflection of that recorded on the CRF. Where the operator is unable to read the entry the clinical data manager should be notified so that the entry may be clarified with the person who completed the CRF.

Data Validation

Data validation is the application of validation rules to the data. For electronic CRFs the validation rules may be applied in real time at the point of entry. Offline validation may still be required (eg for cross checks between data types).

Data Queries

Where data entered does not pass validation rules then a data query may be issued to the investigative site where the clinical trial is conducted to request clarification of the entry. Data queries must not be leading (ie they must not suggest the correction that should be made). For electronic CRFs only the site staff with appropriate access may modify data entries. For paper CRFs the Clinical Data Manager will apply the data query response to the database and a copy of the data query is retained at the investigative site.

Central Laboratory Data

Samples collected during a clinical trial may be sent to a single central laboratory for analysis. The Clinical Data Manager will liaise with the central laboratory and agree data formats and transfer schedules. The sample collection date and time may be reconciled against the CRF to ensure that all samples collected have been analysed.

Other External Data

Analysis of clinical trail data may be carried out by laboratories, image processing specialists or other third parties. The Clinical Data Manager will liaise with such data providers and agree data formats and transfer schedules. Data may be reconciled against the CRF to ensure consistency.

Serious Adverse Event Reconciliation

The CRF will collect Adverse Events reported during the conduct of the clinical trial however there is a separate process which ensures that Serious Adverse Events are reported quickly. The Clinical Data Manager must ensure that data is reconciled between these processes.

Patient Recorded Data

Where the subject is required to record data (eg daily symptoms) then a diary will be provided for completion. Data management of this data requires a different approach to CRF data as, for example, it is generally not practical to raise data queries. Patient diaries may be developed in either paper or electronic (eDiary) formats. Such eDiaries generally take the form of a handheld device which enables the subject to enter the required data and transmits this data to a centralised server.

Database Finalisation and Extraction

Once all expected data is accounted for, all data queries closed, all external data received and reconciled and all other data management activities complete the database may be finalised.

Metrics and Tracking

Typical reports generated and used by the Clinical Data Manager will include:

• Status of page completion / missing pages
• Status of data queries
• Data queries not resolved within specified time limit
• Commonly raised data queries (to help identify areas where improvements can be made)

Quality Control

Quality Control is applied at various stages in the Clincal Data Management process and is normally mandated by SOP.

External links

• Association for Clinical Data Management A not-for-profit organisation that represents and supports professionals involved with managing clinical data from within the pharmaceutical, biotechnology and academic research fields.
• Society for Clinical Data Management Dedicated to promoting quality and excellence in the field of clinical data management.