A Regulatory Perspective on Electronic Data Capture IMMPACT XVIII Meeting June 4, 2015, Washington, DC Sarrit Kovacs, Ph.D. Clinical Outcome Assessments Reviewer COA Staff/OND/CDER/FDA

Disclaimer The views expressed in this presentation are those of the speaker, and do not necessarily represent an official FDA position.

Clinical outcome assessments (COAs) Overview Clinical outcome assessments (COAs) Types Modes of administration FDA Review of Electronic COAs (eCOAs) Regulations governing electronic data capture Guidance for Industry Regulatory standards Other guidelines

Clinical Outcome Assessments (COAs) COAs include: Patient-Reported Outcome (PRO) Clinician-Reported Outcome (ClinRO) Observer-Reported Outcome (ObsRO) Performance Outcome (PerfO) Electronic data capture principles and considerations discussed focus on COA data collection intended to support primary or secondary endpoints in clinical trials But may apply to other types of data collection as well

Modes of Administration of COAs Paper Electronic Interactive Voice Response System (IVRS) Web- or browser-based Tablet Personal device (e.g., smartphone)

Some Advantages of Electronic Over Paper Less risk of data error (less human error) Direct transmission of electronic data may reduce risk to data integrity Less risk of missing data Potential for greater patient compliance (alarms, date/time stamps)

FDA Review of Electronic COAs (eCOAs) Just as with paper COAs, documentation of development and validation of eCOAs is needed for review of evidence to support labeling claims FDA’s PRO Guidance describes good measurement principles for developing PROs, some may be applicable to other COA types Provides an optimal approach; both flexibility and judgment are necessary to meet practical demands of drug development With eCOA, additional documentation may be important to review, such as: Design features Usability testing Training materials for use of the device Documentation related to reformatting from paper to electronic

Device-Specific Regulatory Issues Comparability of data obtained via different collection formats BYOD (patient’s personal device) versus site-provided device Device should be available to entire enrolled population Assure that replacement devices available in case of device failure or lost device (avoid missing data) Data entry date/time stamp documentation

Data-Related Regulatory Issues Sponsors and investigators must ensure that FDA regulatory requirements are met for record keeping, maintenance, and access These responsibilities are independent of method used to record data (paper/electronic) Sponsors should establish appropriate system and security controls Sponsors should establish database backup Sponsors should take steps to avoid premature or unplanned access to unblinded data

Who Controls the Data? Direct control over source data should be maintained by investigator so that verification of source data can occur at the time of FDA inspection. (Avoid source document control by sponsor exclusively) The clinical trial protocol (or another document) should specify how the eCOA source data will be maintained and how the investigator will meet the regulatory requirements.

Audit Trails Direct eCOA data transmission from the eCOA data collection device to the sponsor, clinical investigator, or other 3rd party must include an electronic audit trail that documents all changes to the data after it leaves the electronic data collection device.

Available FDA Guidance for Industry on EDC FDA’s PRO Guidance Describes specific concerns when using electronic instruments; sponsor and investigator responsibilities; things to avoid Computerized Systems Used in Clinical Investigations “provides to sponsors, CROs, data management centers, clinical investigators, and IRBs, recommendations…applies to records in electronic form that are used to create, modify, maintain, archive, retrieve, or transmit clinical data required to be maintained or submitted to the FDA” Electronic Source Data in Clinical Investigations “…recommendations to sponsors, CROs, clinical investigators, and others…ensuring the reliability, quality, integrity, and traceability of data from electronic source to electronic regulatory submission” These two latter guidance documents are to be used together.

FDA Regulatory Standards, and Other Guidelines Addressing EDC 21 CFR Part 11 “Electronic Records; Electronic Signatures” Criteria under which FDA considers electronic records/signatures to be trustworthy, reliable, generally equivalent to paper records Requires FDA-regulated sponsors to implement controls, system validations, audit trails, authority checks, electronic signatures, and device and system checks 21 CFR Parts 312 (drugs) and 812 (devices) Regulations apply equally to both paper records and electronic records General and specific responsibilities for sponsors and investigators Record keeping, maintenance, monitoring, and allowing FDA access/investigation ICH Guideline for Good Clinical Practice E6 (R1) - Section 5.5.3

References and Links Coons SJ, Gwaltney CJ, Hays RD, Lundy JJ, Sloan JA, Revicki DA, Lenderking WR, Cella D, Basch E; ISPOR ePRO Task Force. Recommendations on evidence needed to support measurement equivalence between electronic and paper-based patient-reported outcome (PRO) measures: ISPOR ePRO Good Research Practices Task Force report. Value Health. 2009 Jun;12(4):419-29. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071975.pdf Guidance for Industry: Computerized Systems Used in Clinical Investigations http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf Guidance for Industry: Electronic Source Data in Clinical Investigations http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm328691.pdf

References and Links cont’d. 21 CFR Part 11 “Electronic Records; Electronic Signatures” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=11.10 21 CFR Part 312 (INDs) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=312 21 CFR Part 812 (Devices) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=812 ICH Guideline for Good Clinical Practice E6 (R1) http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf ePRO Consortium http://c-path.org/programs/epro/

Backup Slides

FDA Review of Electronic COAs (eCOAs) Considerations when reformatting an existing paper COA to electronic mode of administration: These switches are evaluated as a modified instrument Cognitive debriefing can be used to ensure the content validity of the COA is not altered when switching the mode. Some things that will likely change are: One item per screen vs. multiple items on a page Skip patterns Alarms Forced response New respondent instructions and training materials

Type of Additional Testing Depends on Size of Change Coons SJ, Gwaltney CJ, Hays RD, Lundy JJ, Sloan JA, Revicki DA, Lenderking WR, Cella D, Basch E; ISPOR ePRO Task Force. Recommendations on evidence needed to support measurement equivalence between electronic and paper-based patient-reported outcome (PRO) measures: ISPOR ePRO Good Research Practices Task Force report. Value Health. 2009 Jun;12(4):419-29. - Adapted from Shields A, Gwaltney C, Tiplady B, et al. Grasping the FDA’s PRO Guidance. Appl Clin Trials 2006;15:69–72.