Overarching Issues for Registries – Overview of Key Regulatory Issues

1. Overarching Issues for Registries – Overview of Key Regulatory Issues CAPT Jim Saviola, OD Director, Division of Bioresearch Monitoring Office of Compliance CDRH October 15, 2014

2. BIMO Program Objectives • Protect the rights, safety and welfare of subjects in FDA-regulated trials. • Determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications. • Assess compliance with FDA’s regulations governing the conduct of clinical trials, including those for informed consent and ethical review.

3. Bioethics – Foundation The Belmont Report (1979) – Ethical Principles • Respect for Persons –Individuals should be treated as autonomous agents. Persons with diminished autonomy are entitled to protection. • Beneficence –Do not harm. Maximize possible benefits and minimize possible harms. • Justice– Who should receive benefits of research and bear its burdens? Equal distribution among subjects.

4. Boundaries Between Practice and Research “Practice" refers to interventions that are designed solely to enhance the well-being of an individual patient that have a reasonable expectation of success. • Provide diagnosis, preventive treatment or therapy to particular individuals. “Research" designates an activity designed to test an hypothesis, permit conclusions to be drawn, and develop or contribute to generalizable knowledge. • Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.

5. Bioethics –Regulations • “ The Common Rule” –45 CFR 46 –Basic Policy for the Protection of Human Research Subjects – Applies to all research supported or conducted by HHS • Institutional Assurances – institution’s commitment to following regulations • IRB Review – initial and continuing • Informed Consent – full disclosure of risk/benefits, participation voluntary, comprehension of study 5

6. Bioethics at FDA –Regulations 6

7. Embedding an IDE in a Registry7 A’s to Consider • Agreement to participate: Informed consent (50.20) • Accountability of study subjects: Minimize subject withdrawals & lost to follow-up • Accumulation of data: Minimize missing and incomplete information • Accuracy of data collection and recording • Auditing & monitoring of study data and study sites • Access to data (e.g., investigators, industry, FDA, CMS) • Adjudication of events (Dr. Andrew Farb – ODE/DCD; Karen Ulisney-OC/BIMO) 7 For Internal Use Only - Do Nor Further Distribute

8. Registry Design Considerations • Data Quality Capacity • Monitoring • Remote plan: completeness, sensible data entry • Auditing • Accuracy of source information, • “Seamless interoperability” = electronic “data bridges” • Transparency & Accountability • Subjects/Patients right to understand how their data is being used 8 For Internal Use Only - Do Nor Further Distribute

9. 21 CFR Part 11 Electronic Records and Signatures • September 2013 (eSource) Electronic Source Data in Clinical Investigations • May 2007 Computerized Systems in Clinical Investigations • August 2003 Part 11, Electronic Records; Electronic Signatures

10. 21 CFR Part 812 Responsibility • Sponsor responsibility – doesn’t translate with delegation to Contract Research Organization or 3rd Party entity (ie; Registry) • Demonstrate that the investigation is scientifically sound. • Obtain FDA and IRB approval • Selecting qualified investigators • Monitoring • Reporting – adverse events, status of study

11. 21 CFR Part 812 Responsibility • Clinical Investigator –Has responsibility for conduct of the study at that site • Responsible for protecting the rights, safety, and welfare of subjects • Obtaining informed consent w/updated IRB approved ICF • Supervision of device use and accountability • Maintain accurate and complete records

12. 21 CFR Part 814 Premarket Approval of Medical Devices • Denial of Approval – 814.45(a)(5) • Withdrawal of Approval – 814.46(a)(4) FDA may issue an order denying/withdrawing approval If any clinical investigation involving human subjects subject to IRB (part 56) or informed consent (part 50) was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.