1. Mark A. Del Vecchio Director, Regulatory and Clinical Affairs Digene Corporation How to Work with FDA: Industry Perspective IVD Roundtable/OIVD Workshop 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 FDA General 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 FDA General 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 FDA Before 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 FDA Before 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 FDA Before 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 FDA Before 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 FDA Before 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.  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 Interaction with FDA During the Review

11.  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 Interaction with FDA During the Review

12.  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 Interaction with FDA In the Home Stretch

13.  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 Interaction with FDA In the Home Stretch

14. Meeting with FDA  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 Recommended points in the process to meet with FDA (teleconference or face-to-face):

15. Meeting with FDA  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 Recommended points in the process to meet with FDA (teleconference or face-to-face):

16.  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 Meeting with FDA Whenever you teleconference with FDA :

17.  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 Meeting with FDA Whenever you meet face-to-face with FDA :

18.  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 Meeting with FDA Whenever you meet face-to-face with FDA :

19.  Serves to resolve any miscommunication immediately  Helps facilitate clear understanding of action items and time commitments 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

20.  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 Utilizing Consultants

21.  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 Quality of Submitted Documents

22.  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 Quality of Submitted Documents It is imperative that your documents are:

23.  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 Quality of Submitted Documents

24.  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 Quality of Submitted Documents

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