How to Work with FDA: Industry Perspective
IVD Roundtable/OIVD Workshop
Mark A. Del Vecchio
Director, Regulatory and Clinical Affairs
Digene Corporation
April 22, 2003
[Powerpoint]
Discussion Topics
- Interaction with FDA
- General Considerations
- Before you Submit
- During the Review
- In the Home Stretch
- Meetings with FDA
- Use of Consultants
- Quality of Submitted Documents
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
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
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
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
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
Interaction with FDA
Before you Submit
- Be prepared
- Use CDRH/CBER Guidance Documents
- Review Other Clearance/Approval Information
- Talk with other Industry RA professionals:
- Utilize regulatory and statistical consultants where appropriate
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
Interaction with FDA
During 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
Interaction with FDA
During 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 FDA
In 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
Interaction with FDA
In 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
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
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
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
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
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
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
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
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
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
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
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
All of these lead to:
- Frustration
- Misunderstandings
- Unnecessary, redundant communications
- Multiple Review cycles
Increased review times
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