Mark A. Del VecchioDirector, Regulatory and Clinical Affairs

Digene Corporation

How to Work with FDA:Industry Perspective

IVD Roundtable/OIVD Workshop

April 22, 2003

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

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

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

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

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

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

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

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

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 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

Interaction with FDADuring the Review

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 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

Interaction with FDAIn the Home Stretch

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):

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):

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 :

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 :

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 :

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

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

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

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 DocumentsIt is imperative that your documents are:

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

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

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