1. Draft Guidance for Industry Electronic Source Documentation in Clinical Investigations FDA Guidance Overview

2. Electronic Source Documentation in Clinical Investigations

3. Draft Guidance Draft- not binding Comments invited in docket Comment period closes Apr 7 Link to the docket – www.regulations.gov www.regulations.gov – Docket # FDA-2010-D-0643

4. Outline Reasons for writing this guidance Electronic Source Documents and Source Data – Data Entry – Data Review – Data Processing and Transmission Regulatory Review Collaboration Conclusions

5. 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

6. 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

7. Process Overview

8. Tier One Data Entry

9. 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

10. 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)

11. 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

12. 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.

13. Example of Data Elements and Data Element Identifiers Field in CRFData ElementData Element Identifier Patient ID#AD0012Randomization algorithm in central computer/June 1 st, 2008/3.00 pm AD0012 SexMaleInvestigator Dr R Smith/June 1 st, 2008/10.53 am AD0012 Age25 yearsInvestigator Dr R Smith/June 1 st, 2008/10.53 am AD0012 Hemoglobin15.3 g/lCo-op labs/June 2 nd, 2008/12:06 pm AD0012 Date blood was drawn for Hemoglobin determinationJune 1 st, 2008Investigator Dr R Smith/June 1 st, 2008/10.53 am AD0012 Radiological report“Right upper lobe consolidation”Dr P Brown, radiological associates/ June 1 st, 2008/4.12 pm AD0012 Blood pressure124/88AB instrument systems/ June 1 st, 2008/10.53 am AD0012 Concomitant medicationsLasix 40mg QDInvestigator Dr R Smith/June 1 st, 2008/10.53 am AD0012

14. 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)

15. 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

16. Example of Modification/Correction Field in CRFData ElementData 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

17. Tier 2 - Data Review

18. 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

19. Tier 3 Data Processing and Transmission

20. 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

21. 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

22. 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

23. 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