Data Quality & Monitoring Using NCDR for an IDE An FDA View

1. Data Quality & Monitoring Using NCDR for an IDEAn FDA View Andrew Farb, MD and Dorothy Abel, BSBME Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) Trans-Radial Education and Therapeutics (TREAT) IV FDA Headquarters Silver Spring, MD 29 July 2013 1

2. Conflict of Interest No conflicts of interest to report. 2

3. Potential Advantages of an IDE Embedded in an NCDR Registry • Real-world enrollment/treatment • Potential efficiencies • Electronic data capture • Standard medical records dataset per NCDR • Cath/PCI data already being collected per routine • Sites already experienced in data collection and familiar with the CRF • Time and cost savings

4. Embedding an IDE in an Ongoing Registry5 A’s to Consider • Accumulation of data (Minimize missing data) • Accuracy of data • Adjudication of data • Auditing & monitoring of data • Access to data

5. What is Clinical Study Monitoring? • Methods used to oversee the conduct of, and reporting of data from, clinical investigations • Focus should be on the processes that are critical to: • Protecting human subjects • Maintaining the integrity of study data • Compliance with applicable regulations • Intended to identify and correct practices that could result in inadequate patient protection and/or poor data quality

6. Sponsor Responsibility • Provide oversight to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality and integrity of the resulting data submitted to FDA* • Although sponsors can transfer responsibilities for monitoring to a 3rd party, they are ultimately responsible for ensuring adequate monitoring *21 CFR part 312, subpart D generally (Responsibilities of Sponsors and Investigators) and 21 CFR part 812, subpart C generally (Responsibilities of Sponsors)

7. Is There a Prescription for Study Monitoring? • The FDA regulations are not specific about how sponsors are to conduct monitoring of clinical investigations • Typical monitoring • For pivotal IDEs, often frequent (every 4-8 weeks) visits to clinical sites to evaluate study conduct and review data for enrolled subjects • For other types of studies: • Less frequent (every 2-3 years) to qualify/certify sites to ensure they have the resources, training and safeguards to conduct clinical trials • No regular on-site monitoring; instead, reliance on centralized and alternative monitoring methods

8. What Needs to be Monitored in an IDE Study? • Data critical to the reliability of the study findings • Data that support primary and secondary endpoints • Data critical to subject safety • Subject eligibility criteria • SAEs and unanticipated AEs, deaths, and withdrawals, especially when a withdrawal may be related to an adverse event • Processes critical to subject safety and ethical treatment • E.g., seeking appropriate medical consultation or scheduling extra visits in the event of specified clinical or laboratory findings • Processes critical to data integrity • E.g., referring specified events for adjudication

9. Focus of Monitoring Activities • Verification that the informed consent was obtained appropriately • Procedures for documenting accountability and administration of the investigational product • E.g., ensuring the integrity of randomization at the site level, when applicable • Less important data and processes often may be monitored less intensively and frequently.

10. FDA’s Role • Reviews monitoring plan • Conducts on-site inspections to assess the protection and safety of subjects and to validate data submitted in new drug applications (NDAs), biologics license applications (BLAs), and device premarket approval (PMA) applications • Sponsors • Clinical investigators • Contract research organizations (CROs) • Institutional review boards (IRBs)

11. Obtaining High Quality Study Data • A well-designed and executed study protocol is the most important tool for ensuring high-quality data with human subject protection. • Poorly designed or ambiguous protocols or CRFs can introduce systemic errors leading to an unreliable clinical investigations despite rigorous monitoring. • Study-specific training of investigators, other site staff, and monitors contributes significantly to study quality. • Independent of how or where data will be collected.

12. Developing the Clinical Study Protocol for IDE Approval • Early interaction with the pre-market DCD Review team utilizing the the Pre-Submission process • Well designed study protocol • Clear study objectives • Clinically relevant and assessable primary and secondary endpoints • Appropriate enrollment criteria and subject follow-up assessments • Pre-specified study hypotheses and statistical analysis plan • CRFs that capture essential clinical and device-specific information • Acceptable informed consent document

13. Issues Associated With Use of a Multicenter Registry Infrastructure to Collect Data Under an IDE • What clinical sites/operators will participate? • Identify sites with high rates of complete and accurate data collection • Identify operators with appropriate training and experience with low complication rates • The investigator is responsible for protecting the rights, safety, and welfare of subjects. • An investigator must conduct the investigation in accordance with the signed agreement with the sponsor, the investigational plan, the IDE regulation and other applicable FDA regulations, and any conditions of approval imposed by an IRB and FDA. (§812.100) • Some sites/operators which excel in clinical care may not be the same as those which excel in clinical research, and vice versa

14. Issues Associated With Use of a Multicenter Registry Infrastructure to Collect Data Under an IDE slide 1 • What CRF fields will need to be modified or added for study and device-specific data collection? • Adjunctive imaging (angio, IVUS, OCT) metrics • Protocol required post-PCI cardiac biomarkers measurements • Medium and longer-term study subject clinical follow-up assessments

15. Issues Associated With Use of a Multicenter Registry Infrastructure to Collect Data Under an IDE slide 2 • Need to prevent or minimize of selection bias • Particularly important in non-randomized studies • Need clarity on when data are collected & entered into CRFs • Retrospective or in real time? • What entity will serve as the study sponsor and thus be responsible for monitoring?

16. Issues Associated With Use of a Multicenter Registry Infrastructure to Collect Data Under an IDE • Need assurance that all important data, particularly adverse events, are documented and accurately entered into CRFs • Identify who will compare source records and entered data • Provisions for assembling source materials and preparing narrative summaries • Event adjudication by an independent CEC • Preparation of study materials for FDA audits including patient identifiers • Clarify what entity owns the data and who has access to the data for presentation, publication, and regulatory submissions • Industry, investigators, and/or professional society • Will industry sponsor an embedded IDE and be willing to share access with other parties?

17. An IDE Application is Much More Than a Report of Prior Investigations and an Investigational Plan • Labeling • Promotion restrictions • Commercialization restrictions • Import and export limitations • Signed investigator agreements • Supplemental applications • IRB certification • Control of devices • Informed consent reporting

18. Parting Thoughts on Monitoring a Multicenter Registry Infrastructure to Collect Data Under an IDE • No expectation of special waivers because the study is being run by a 3rd party • Still need to be able to trace back to source data • The submission will look like any other IDE with respect to data quality and monitoring unless vetted and agreed-upon exceptions are identified by regulatory stakeholders • IDE Staff • Bioresearch Monitoring Program (BIMO)