Draft Guidance for IndustryElectronic Source Documentation in

Clinical Investigations

FDA Guidance Overview

Electronic Source Documentation in Clinical Investigations

Draft Guidance

Draft- not binding Comments invited in docket Comment period closes Apr 7 Link to the docket

– www.regulations.gov– Docket # FDA-2010-D-0643

Outline

Reasons for writing this guidance Electronic Source Documents and Source Data

– Data Entry– Data Review– Data Processing and Transmission

Regulatory Review Collaboration Conclusions

Why Did We Write This Guidance?

Difficulty with paper based studies– Burden of transcription errors– Monitoring– Archival and transporting of bulky CRF’s around the world

Advantages of electronic platform– Eliminate unnecessary duplication of data – Reduce transcription errors– Promote real time entry of data during visits– Prompts for missing data and data errors will ensure accuracy and

completeness– Potential interface with medical devices, electronic health records,

laboratory data, imaging systems, etc…– Rigorous audit trail

Three-Tiered Process

For discussion purposes we have divided the process into three tiers– Tier 1- collection and entry of data– Tier 2- data review– Tier 3- data processing and transmission

Process Overview

Tier One

Data Entry

Data Elements

A data element represents a single observation associated with a subject in a clinical study e.g. – Birth date– WBC Count– Pain severity measurement

New Data elements- for data elements created at the time of data entry, the electronic case report form is the source document

– (No other record of that data element is needed) Blood pressure Temperature resolution of a symptom or sign Laboratory measurement of hemoglobin

Data elements that are transcribed from another document e.g. progress note by physician instrument printout Blood pressure

– the source document must be maintained Corroborative data may be requested by FDA during a site inspection depending on context e.g.

evidence of blood glucose readings to corroborate a diagnosis of diabetes

Data Originators

Various parties (originators) may be authorized to enter data elements

– Investigators, study site staff– biomedical devices– Automated laboratory reporting systems– Imaging facilities– Electronic health records– Clinical study subjects (PRO)

List of Authorized Data Originators

Each study site should maintain a list of authorized data originators (persons, devices, instruments..)

– The list should include the unique user name assigned to the data originator, and the period for which authorization is given

– The site should employ controls to ensure security and integrity of user names and passwords

– Users should accept responsibility for the validity of the data they enter

Data Element Identifiers

Are pieces of electronic information that are linked to a data element

Data element identifiers should include:1. The originators of data elements, including those

entered manually (e.g., by the investigator), and automatically (e.g., from a device or instrument)

2. The date and time the data elements are entered into the eCRF

3. The study subject to whom the data elements belong.

Example of Data Elements and Data Element Identifiers

Field in CRF Data Element Data Element Identifier

Patient ID# AD0012 Randomization algorithm in central computer/June 1st, 2008/3.00 pm

AD0012

Sex Male Investigator Dr R Smith/June 1st, 2008/10.53 am AD0012

Age 25 years Investigator Dr R Smith/June 1st, 2008/10.53 am AD0012

Hemoglobin 15.3 g/l Co-op labs/June 2nd, 2008/12:06 pm AD0012

Date blood was drawn for Hemoglobindetermination June 1st, 2008 Investigator Dr R Smith/June 1st, 2008/10.53 am AD0012

Radiological report “Right upper lobe consolidation” Dr P Brown, radiological associates/ June 1st, 2008/4.12

pm AD0012

Blood pressure 124/88 AB instrument systems/ June 1st, 2008/10.53 am AD0012

Concomitant medications Lasix 40mg QD Investigator Dr R Smith/June 1st, 2008/10.53 am AD0012

Display of Data Element Identifiers

The electronic system should include a functionality that enables users to reveal the data element identifiers (e.g. by cursor placement or view mode displaying data element with its identifiers)

Modifications and Corrections

Modified data elements should carry new, write-protected data element identifiers reflecting:

– the originator of the modified element– the date and time of the change– a text field describing the reason for the change is

recommended The original data element and its identifiers should be

preserved

Example of Modification/Correction

Field in CRF Data Element Data Element Identifier

Hemoglobin 12.3gm/dl Modified by: Investigator assistant Dr B Green/July 7th, 2008/9.00

am/AD0012

Reason: Data error reported by Co- op labs July 6th 2008 due to standardization problem; sample was retested

Original data (write-protected automated

carryover): Hemoglobin 15.3gm/dl (Co-op labs/June 2nd,

2008/noon)/AD0012

Tier 2

- Data Review

Investigator Responsibilities

“Investigator is responsible for conducting the study according to the protocol and for protecting the rights safety and welfare of study subjects”

The investigator’s copy of the CRF– Contains all data elements that the investigator has reviewed– It should permanently carry proof of the investigator’s sign off– A write-protected copy should be stored– The investigator should maintain control of this copy– (In exceptional circumstances the protocol may require that certain data

elements be hidden from the investigator) Archived eSource documents should be available in read-only format to the

originators who submitted them

Tier 3

Data Processing and Transmission

Transmission and archiving of data

Electronic data entry provides an opportunity for the sponsor to transmit data real-time to designated parties

– Examples: real-time transmission of critical safety data to data safety monitoring board, real-time transmission of site performance data to CRO

Blinding should not be compromised A detailed plan for data transmission should be described by

the sponsor

Sponsor Responsibilities

Protocol should include information about the intended use of computerized systems during the conduct of a clinical study

– Description of the security measures employed to protect the data

– Detailed diagram and description of the transmission of electronic data

Describe electronic tools intended to be used to detect events in the eCRF such as, but not limited to, data inconsistencies, missing data, and entries out of range

Regulatory Review Collaboration

FDA’s review divisions are available to review sponsors’ plans for handling electronic source data

Typically discussed with FDA during:– Pre IND/IDE meetings– End of Phase II/Special Protocol Assessment– Pre NDA/BLA/PMA meetings

Conclusions

Electronic platforms for clinical investigations have enormous potential advantages

– Improvement in trial quality and safety, simpler monitoring, reduced errors, real time information flow, central data monitoring, incorporation of data from instruments, simpler archival

The success of this approach depends on dependable procedures and controls to ensure reliability of the source data

FDA is hopeful that this draft guidance will be an important step to facilitate adoption of electronic data gathering across the medical product industry