1. Preparation for FDA Advisory Committee Meetings Robert M. Kirsch, RAC Vice President, Regulatory Affairs TolerRx Inc. Cambridge, MA

2. Agenda “Standard” FDA Meetings “Standard” FDA Meetings Part of Everyday Life for Regulatory Affairs Part of Everyday Life for Regulatory Affairs Advisory Committee Meetings Advisory Committee Meetings For Many, A “Once in a Lifetime Opportunity”! (For Some, More Than Once) For Many, A “Once in a Lifetime Opportunity”! (For Some, More Than Once)

3. Standard FDA Meetings Confidential Discussion Confidential Discussion Audience  FDA Audience  FDA Pre-IND, End-of-Phase 2, pre-NDA / BLA Pre-IND, End-of-Phase 2, pre-NDA / BLA Driven by Sponsor-Generated Questions Driven by Sponsor-Generated Questions Variety of Topics at Various Stages of Product Development Variety of Topics at Various Stages of Product Development Guidance on FDA / Sponsor Meetings Guidance on FDA / Sponsor Meetings

4. Advisory Committee Meeting Very Different Forum – Public Discussion Very Different Forum – Public Discussion Audience  Advisory Committee Members (Independent Experts Selected by FDA) Audience  Advisory Committee Members (Independent Experts Selected by FDA) Driven by FDA-Generated Questions Driven by FDA-Generated Questions Clinical / Statistical Discussions of Safety & Efficacy Clinical / Statistical Discussions of Safety & Efficacy

5. Advisory Committee Meeting Balanced Presentation of Issues Balanced Presentation of Issues Sponsor Presents Position; Q&A Sponsor Presents Position; Q&A FDA Presents Position; Q&A FDA Presents Position; Q&A Open Public Hearing (e.g., Patient Groups) Open Public Hearing (e.g., Patient Groups) Committee Deliberations Committee Deliberations Committee Votes on Questions Posed by FDA Committee Votes on Questions Posed by FDA

6. Advisory Committee Meeting First Steps (1) Identify the Appropriate Team Composition Identify the Appropriate Team Composition Team Leader (e.g., Regulatory Affairs) Team Leader (e.g., Regulatory Affairs) Potential Presenters Potential Presenters Data Experts (e.g., Clinicians, Statisticians) Data Experts (e.g., Clinicians, Statisticians) Outside Experts / Consultants (e.g., KOL) Outside Experts / Consultants (e.g., KOL) Other Support (e.g., Medical Writers, Administrative Assistants, IT) Other Support (e.g., Medical Writers, Administrative Assistants, IT) Establish Clear Roles and Responsibilities Establish Clear Roles and Responsibilities

7. Advisory Committee Meeting First Steps (2) Need for Intensive Preparation – Not Like Any Other Meeting! Need for Intensive Preparation – Not Like Any Other Meeting! Block Out Calendars (Months to Prepare!) Block Out Calendars (Months to Prepare!) Arrange Off-site Preparation Meetings (e.g., Several Multiple-day Meetings) Arrange Off-site Preparation Meetings (e.g., Several Multiple-day Meetings) No Interruptions (e.g., No Cell Phones, e-mail, or PDAs) No Interruptions (e.g., No Cell Phones, e-mail, or PDAs) CRITICAL – Determine Your Company’s Discipline! CRITICAL – Determine Your Company’s Discipline! Internal Preparation or Off-site With Consultants Internal Preparation or Off-site With Consultants

8. Advisory Committee Meeting Know Your Data! Understand the FDA’s Point of View, Concerns, and Issues Understand the FDA’s Point of View, Concerns, and Issues “Why an Advisory Committee?” “Why an Advisory Committee?” NCE, New Drug Class, Public Health Issues, Use of Surrogate Endpoints NCE, New Drug Class, Public Health Issues, Use of Surrogate Endpoints Review Product File’s Regulatory History (e.g., Letters, Telephone Records) Review Product File’s Regulatory History (e.g., Letters, Telephone Records) Take a Fresh Look at All the Data Take a Fresh Look at All the Data

9. Advisory Committee Meeting Know Your Data!! Are There Perceived or Potential... Are There Perceived or Potential... Safety Issues? Safety Issues? Efficacy Issues? Efficacy Issues? Statistical Issues? Statistical Issues? Know Your Position on Every Issue Know Your Position on Every Issue

10. Advisory Committee Meeting Know the Audience – Do Research! Varying Disciplines Varying Disciplines Practicing / Academic Physicians, Nurses Practicing / Academic Physicians, Nurses Statisticians Statisticians Consumer and Industry Representatives Consumer and Industry Representatives Varying Levels of Specific Disease Understanding Varying Levels of Specific Disease Understanding Obtain Biographies of Committee Members Obtain Biographies of Committee Members Obtain Transcripts of Previous Meetings and Voting Records Obtain Transcripts of Previous Meetings and Voting Records Obtain Literature and Publications Obtain Literature and Publications Varying Levels Of Product Understanding Varying Levels Of Product Understanding Investigator in Product’s Clinical Study vs No Knowledge of Product Investigator in Product’s Clinical Study vs No Knowledge of Product

11. Advisory Committee Meeting Information Package Target the Audience Target the Audience Find Balance Between “Lecturing” and “Educating” Find Balance Between “Lecturing” and “Educating” Scientific Discussion of Data Supported by Peer-Reviewed Literature, as Appropriate Scientific Discussion of Data Supported by Peer-Reviewed Literature, as Appropriate Discuss FDA’s Position / Issues and Provide Scientifically-Based Explanations Discuss FDA’s Position / Issues and Provide Scientifically-Based Explanations Clear, Concise, Unambiguous Clear, Concise, Unambiguous Releasable to Public Releasable to Public Don’t Include Proprietary Information Don’t Include Proprietary Information

12. Advisory Committee Meeting Presentation Target the Audience Target the Audience Use Information Package as Basis for Preparing Presentation Use Information Package as Basis for Preparing Presentation Address FDA’s Position / Issues and Present Scientifically-Based Responses Address FDA’s Position / Issues and Present Scientifically-Based Responses Be Clear; Keep to the Point Be Clear; Keep to the Point The Panel Has Reviewed the Information Package in Advance The Panel Has Reviewed the Information Package in Advance

13. Advisory Committee Meeting Q&A Preparation Most Difficult Part of the Meeting and Requires Most Preparation Most Difficult Part of the Meeting and Requires Most Preparation Anticipate Every Question (>50 Questions) Anticipate Every Question (>50 Questions) Review FDA’s Information Package Review FDA’s Information Package Generate Questions From Issues Identified by FDA and by the Team Generate Questions From Issues Identified by FDA and by the Team Write a Response to Every Question Write a Response to Every Question

14. Advisory Committee Meeting Q&A Preparation Develop Backup Slides, as Necessary, to Support Responses (Hundreds of Slides) Develop Backup Slides, as Necessary, to Support Responses (Hundreds of Slides) Use Data Experts as Backup Slide Callers Use Data Experts as Backup Slide Callers Presenters and Data Experts Memorize the Responses and Related Backup Slide Call Numbers Presenters and Data Experts Memorize the Responses and Related Backup Slide Call Numbers

15. Advisory Committee Meeting Practice, Practice, Practice!! Again, Practice at Offsite Location (No Interruptions) – Recommend at Least 4 Sessions of 3 to 4 Days Each Again, Practice at Offsite Location (No Interruptions) – Recommend at Least 4 Sessions of 3 to 4 Days Each Conduct Several Mock Advisory Sessions Conduct Several Mock Advisory Sessions Videotape Practice Sessions and Review Performance Videotape Practice Sessions and Review Performance

16. Advisory Committee Meeting Practice, Practice, Practice Some More! Utilize Slide Presentation Technology With Multiple Laptops, Preview and Main Screens Utilize Slide Presentation Technology With Multiple Laptops, Preview and Main Screens Effectively Manage Stress and Differences of Opinion Effectively Manage Stress and Differences of Opinion Manage Public Relations, Internal Relations and Senior Management Expectations Manage Public Relations, Internal Relations and Senior Management Expectations

17. Advisory Committee Meeting The Day Before Dos Dos Dry-Run of Presentation Dry-Run of Presentation “Light” Q&A Practice “Light” Q&A Practice Keep It Fresh Keep It Fresh Early to Bed! Early to Bed! Don’ts Don’ts Drastically Change Presentation Drastically Change Presentation Change Responses to Questions Change Responses to Questions

18. Advisory Committee Meeting Conclusions Planning and Practice Are Key Planning and Practice Are Key One of the Highest Visibility and Important Events for a Company One of the Highest Visibility and Important Events for a CompanyHowever Also a Chance for a Company to Shine! Also a Chance for a Company to Shine!