1. Summary of Oct. 3 rd Presentations Improving the System of Reporting and Interpreting Unexpected Serious Adverse Events to Investigators Conducting Research Under an IND

2. 2 Goals of Project  Generate empirical evidence about the current U.S. system for reporting unexpected serious adverse events to investigators conducting research under an investigational new drug application  Consider potential modifications of the current system to more efficiently and effectively inform investigators of these events

3. 3 Specific Objectives 1.Document the current range of practices for safety monitoring and reporting of unexpected SAEs to investigators (Workstream 1) 2.Quantify resources required to manage individual expedited safety reports and assess investigators’ perceptions regarding the value of this information (Workstream 2) 3.Compare current practice of submitting individual unexpected SAEs with an alternative approach based on the European Commission's guidance (Workstream 3)

4. 4 Specific Objectives 4. Explore patients' expectations for how investigators should monitor and communicate information about product safety during the conduct of a clinical trial, and explore current practice on how safety monitoring efforts are being conveyed to research participants in the informed consent document (Workstream 4) 5. Integrate results of all workstreams and recommend ways to optimize reporting of SAEs to investigators while ensuring human subjects protection (Workstream 5)

5. 5 Reporting Unexpected, Serious Adverse Events to Investigators Kathleen Uhl FDA Co-Team Leader Susan Ellenberg Univ. of Pennsylvania Co-Team Leader Jose Vega Amgen Co-Team Leader Sundeep Sethi Amgen Workstream 1 Lead Lynda Szczech Duke Clinical Research Institute Workstream 3 Lead Howard Greenberg ACCP/Clinilabs Workstream 2 Lead Kevin Weinfurt Duke Clinical Research Institute Workstream 4 Lead Workstream 1 TeamWorkstream 2 TeamWorkstream 3 TeamWorkstream 4 Team Organization of Project Robert Califf Duke Translational Medicine Institute Workstream 5 Lead Workstream 5 Team Greg Nadzan Project Manager Amgen, Inc. Project Managers Cheri Janning Sr Clinical Project Manager Duke University

6. 6 Workstream 1 Document current range of practices for safety monitoring and reporting unexpected SAEs to investigators  Industry sponsors emphasize safety notifications to investigators using individual expedited reports  Industry sponsors have well-developed mechanisms for IND safety data management including drug safety units/clinicians, written standard procedures, and use of external bodies to manage and review the data  Investigators voiced concerns to sponsors including dissatisfaction with volume (too many) and content (not relevant) of individual IND safety reports  Recommend encouraging aggregate safety notifications from sponsors to investigators and reducing investigator burden of unnecessary individual expedited reports

7. 7 Workstream 2 Quantify resources and assess value of individual expedited safety reports  Resource estimate of $22/SAE evaluated with CI of $10- $33 (0.25hr median with CI of 0.12-0.38 hrs/SAE). Sensitivity analysis gives range of $7-49/SAE.  Low perceived value of individual SAE reports due to lack of context (incidence, relatedness) for events  “Contextual” information is useful:  Data Monitoring Committee (DMC) reports  Notification letter of unanticipated problem (~UADE or suspected adverse reaction in FDA guidances of 1/09 and 9/10)  Increased use of DMCs and FDA Guidance may assist investigators, sponsors, and IRBs focus on events likely to impact patient safety

8. 8 Workstream 3 Compare current practice of submitting individual expedited reports with alternative approach used in European Union  Small number of respondents and small number of reportable events in this workstream limit conclusions  Data suggest a potential time savings afforded to investigators by aggregate reporting of individual events

9. 9 Workstream 4 Explore patients’ expectations for safety monitoring and communication as well as how safety monitoring efforts are being conveyed to participants in the informed consent document Recommendations:  Increase patients’ understanding about clinical trials and how risks are managed  Language in consent forms should reflect reality  Need to address conflicts of interest to restore/maintain trust

10. 10 Objectives of October 3 rd /4 th meeting (see Agenda)  Discuss and integrate empirical findings from all components of this project  Consider implications of the US FDA’s new premarket safety regulations  Develop a set of recommendations for optimal reporting of unexpected serious adverse events to investigators that will improve human subjects’ protection

11. 11 Questions to Consider  Can you envision an alternative model for reporting important new safety information to investigators and patients during the conduct of a clinical trial?  How can we better evaluate safety of an investigational product across multiple clinical trials and indications for use?

12. 12 FDA’s new IND Safety Reporting Rule  What are the likely implications of FDA’s new IND safety reporting rule on sponsor practices in reporting to investigators?  What will be the impact of FDA’s new IND safety reporting rule on patients’ perceptions of the adequacy of monitoring and communicating serious adverse events?

13. 13 Workstream 1 Team  Philippe Bishop (Roche)  Dorothy DiChristofano (Sanofi-Aventis)  Leann Fieldstad (Roche)  Suzanne Gagnon (ICON Clinical Research)  Greg Hockel (PharmaNet)  Anne Meeker-O’Connell (FDA)  Greg Nadzan (Amgen)  Diane Ryan (Pfizer)  Sundeep Sethi – Workstream Lead (Amgen)  Jennifer Sorgen (Pfizer)  Jose Vega (Amgen)

14. 14 Workstream 2 Team  Susan Ellenberg (UPenn)  Howard Greenberg – Workstream Lead (ACCP / Clinilabs)  Greg Hockel (PharmaNet)  Kevin Jones (Accurate Clinical Trials)  Greg Nadzan (Amgen)  Janet Norden (FDA)  Diane Ryan (Pfizer)  Miklos Salgo (Roche)  Sundeep Sethi (Amgen)  Lynda Szczech (Duke)  David Vock (Duke)

15. 15 Workstream 3 Team  Suzanne Gagnon (ICON Clinical Research)  Heather Macy (Pfizer)  Rachpal Malhotra (Bristol-Myers Squibb)  Margaret McLaughlin (Pfizer)  Greg Nadzan (Amgen)  Leonard Sacks (FDA)  Sundeep Sethi (Amgen)  Lynda Szczech – Workstream Lead (Duke)  Jose Vega (Amgen)

16. 16 Workstream 4 Team  Kathryn Flynn (Duke)  Kevin Weinfurt – Workstream Lead (Duke)

17. 17 Workstream 5 Team  Robert Califf (Workstream Lead)  Susan Ellenberg  Howard Greenberg  Judith Kramer  Janet Norden  Sundeep Sethi  Kathleen Uhl  Jose Vega