Mark A. Del Vecchio Director, Regulatory and Clinical Affairs Digene Corporation

1. How to Work with FDA:Industry PerspectiveIVD Roundtable/OIVD Workshop Mark A. Del Vecchio Director, Regulatory and Clinical Affairs Digene Corporation April 22, 2003

2. Discussion Topics • Interaction with FDA • General Considerations • Before you Submit • During the Review • In the Home Stretch • Meetings with FDA • Use of Consultants • Regulatory • Statistical • Quality of Submitted Documents

3. Interaction with FDAGeneral Considerations • In the regulatory arena, your Company’s success is highly dependent on your working relationship and reputation with FDA • You have the right and the obligation to work with the Agency on your submission strategies • Be as up front as possible regarding your proposed submission strategy…it is important not to surprise the Agency • Honor the resulting commitments

4. Interaction with FDAGeneral Considerations • Document all of your communications with FDA • This will help both you and FDA to easily refer to specifics of items discussed/agreed upon • Expands internal Company communication, clarifying corporate objectives when addressing issues with FDA • It is imperative that you discuss submission options with the appropriate review branch, particularly when proposing an “express” or novel route

5. Interaction with FDABefore you Submit • Establish which Center/ OIVD Division will review your submission • Determine the appropriate submission type • Discuss your proposed clinical study and submission with FDA review team • Draft Clinical Protocol should be available • Including the statistical analysis plan for the study data

6. Interaction with FDABefore you Submit • It is critical that you have the Intended Use for the test clearly defined • This is the mechanism whereby FDA can determine the appropriateness of your clinical study to support the intended claim(s) • Significant time should be dedicated to ensuring FDA understands your claims and the type of data: • FDA expects to support these claims • You propose will adequately support these claims • Be prepared to provide rationale for the statistical approach to support your claims

7. Interaction with FDABefore you Submit • Agreement on clinical trial design and submission strategy is very important • Amount of upfront discussion dependent on complexity and “unique” nature of the approach • Traditional approach – fewer unknowns • It is appropriate to discuss statistical issues directly with FDA statistician when necessary to minimize confusion or to clarify FDA’s position

8. Interaction with FDABefore you Submit • Be prepared • Use CDRH/CBER Guidance Documents • Review Other Clearance/Approval Information • CDRH/CBER Website • FOI • Talk with other Industry RA professionals: • ADVAMED • AMDM • RAPS • Utilize regulatory and statistical consultants where appropriate

9. Interaction with FDABefore you Submit • Major objectives of earlier interactions - to reach a common understanding with FDA regarding your plan to support the intended use you are evaluating via pre-clinical and clinical studies • Meet with FDA as often as necessary before submission until both parties are comfortable with approach • Minimal goal is to reach philosophical agreement with FDA on the approach, however, things could change • Try to minimize areas that could change as you go along • Bring major changes back to FDA for discussion

10. Interaction with FDADuring the Review • Often times, FDA will request additional information in a fairly informal manner, handled primarily via phone and/or email • Only when the request is substantive will FDA issue a formal deficiency letter or written request for additional information; typically near the end of the review cycle • Try to work with FDA to get more statistical review feedback DURING the review

11. Interaction with FDADuring the Review • Much statistical discussion should take place before submission; however, • sometimes specific details not available until after a decision is made • atypical, but has occurred on several occasions recently • Work with OIVD to ensure that you have the opportunity to address statistical concerns prior to a decision • One reason it is critical to reach some form of agreement on statistical plan before start of the study and prior to submission

12. Interaction with FDAIn the Home Stretch • Just prior to an FDA decision (2-3 weeks) • Most of the technical details worked out…FDA has a good understanding of the results of your clinical study and data available to support application • Much of this time spent on the specific details of the product labeling (PI) • May involve modifying your intended use statement to better reflect study data • The type/extent of data that can be included in the PI will be discussed • Last minute administrative details are addressed

13. Interaction with FDAIn the Home Stretch • Very critical period, since time often running out to make a decision • Respond quickly to FDA requests • Utilize email as much as possible…good means to communicate • Accurate, written record • Very rapid • Can submit hard-copy email comms with final amendment if requested by Reviewer

14. Meeting with FDA Recommended points in the process to meet with FDA (teleconference or face-to-face): • When first formulating your regulatory approach • Submission type • Correct review branch/division • Prior to initiation of clinical study • Draft clinical protocol should be available • Proposed Intended Use • Data analysis plan

15. Meeting with FDA Recommended points in the process to meet with FDA (teleconference or face-to-face): • Prior to Submission • following initial data analysis • particularly if statistical issues were raised during earlier meetings • During the review if necessary • to respond to questions/identified deficiencies with the application

16. Meeting with FDA Whenever you teleconference with FDA : • Provide talking points prior to the call, if time permits • Determine the participants required on the call, both for you and FDA • Sometimes a one-on-one with the Lead Reviewer is best • FDA is very responsive to setting up teleconferences in a timely manner • Gone are the days you could not contact your reviewer for several days

17. Meeting with FDA Whenever you meet face-to-face with FDA : • Provide agenda, talking points, data package prior to meeting at least 1 week in advance • Allow 3-4 weeks to schedule meeting with FDA; schedules are tight and you want all the essential people in the room when discussing your submission • Decide whether a formal presentation is appropriate…recommended approach • Conduct several “rehearsals” in-house prior to the meeting

18. Meeting with FDA Whenever you meet face-to-face with FDA : • Have your regulatory and/or statistical consultants with you for the meeting • FDA will always have a statistician participate in the meeting, particularly if clinical trial design or data analysis is being discussed • Before the meeting, prepare questions (with the responses) you anticipate FDA will ask • Have your technical staff with you as well, particularly to address unanticipated questions from the Review Team

19. Meeting with FDA Follow-up after the meeting with minutes to your Lead Reviewer or a “Memo of Understanding” so that key points and decisions made during the meeting are documented • Serves to resolve any miscommunication immediately • Helps facilitate clear understanding of action items and time commitments

20. Utilizing Consultants • Highly recommended when interacting with FDA, particularly if you: • Are taking a novel approach • New to the industry • Bringing a product to a different review branch/division or Center • Do not have dedicated in-house statistical support • Typically have a greater range of contacts and experience with FDA • Can suggest approaches taken in other Centers or other Divisions within ODE/OIVD • Provide objective external review of submission

21. Quality of Submitted Documents • The success of your submission is greatly dependent on FDA’s ability to read and understand the document • Pre-submission interaction will greatly enhance the quality and clarity of the documents • Respect the fact that FDA reviewers handle several submissions simultaneously and therefore must make very efficient use of time spent on a single submission • Very important that the information in the submission build on an orderly presentation of history, facts, and data

22. Quality of Submitted Documents It is imperative that your documents are: • Well-organized • TOC • Clear, consistent pagination • Labeled section tabs • Thorough, clear, and concise in your descriptions • Use Summary Tables as much as possible • Do not assume FDA “remembers”: • Conversations • Prior submissions • Details of your product

23. Quality of Submitted Documents • If it is critical that a particular point be communicated to FDA, repeat it several times in different sections of the application • Always reiterate important background information • If your submission is lengthy, use this tactic more often • When cross-referencing other submissions or even volumes of same submission, provide a summary of information to eliminate “flipping back and forth” between documents • When responding to specific FDA questions, always restate the question immediately prior to your written response

24. Quality of Submitted Documents • When reviewing documents internally prior to submission, assume no prior knowledge • Have an outside party review documents • Regulatory consultant • Statistical consultant • Another department member within your organization, but not involved in the project

25. Quality of Submitted Documents • Confusing, mis-numbered tables • Poor organization • Improper pagination • Wordy, unclear text All of these lead to: • Frustration • Misunderstandings • Unnecessary, redundant communications • Multiple Review cycles Increased review times