Meetings with FDA Martha A. Feldman, RAC Drug & Device Development Co., Inc. UWE Biomedical Regulatory Affairs Feldman 13 Nov 2007

Topics for this Session FDA’s views on meetings Kinds of Meetings: drug/biotech and medical device products Types of Meetings for PDUFA Products Make request for a meeting Prepare for Meeting Participate in Meeting Follow-up to Meeting Miscellaneous Feldman 13 Nov 2007

FDA’s View of Meetings FDA is committed to communicating and interacting with sponsors FDA believes face-to-face meetings benefit both sponsor and agency FDA believes meetings are cost-effective in the long run for both sponsor and agency This slide and several of the following slides are abstracted from Elisa D. Harvey, “Understanding the Pre-IDE Program: FDA Perspective”, 25 May 2005 http://www.fda.gov/cdrh/present/advamed-052505-harvey/index_files/index.html Feldman 13 Nov 2007

Kinds of Meetings - 1 Drugs and Therapeutic Biologics Pre-clinical Research Meeting Pre-IND Meeting End of Phase 2/Pre-Phase 3 Meeting Clinical Hold Meetings Pre-NDA Meeting Advisory Committee Meeting End of Review Conference Refusal to File Conference Pre-NDA Supplement Meeting Feldman 13 Nov 2007

Kinds of Meetings - 2 Medical Devices Scientific Meeting/Prior to proof of concept animal studies Early Collaboration Meetings (Agreement and/or Determination) Pre-IDE Meeting/Post-feasibility/Pre-Pivotal Study Meeting Informal Pre-IDE Meetings Other Device Meetings Pre-PMA Meeting 100-Day PMA Meetings Post-deficiency letter for 510(k) or PMA Appeal of final decision on PMA, 510(k), IDE disapproval Advisory Committee Meeting Feldman 13 Nov 2007

FDA-SPONSOR MEETINGS - DRUGS Feldman 13 Nov 2007

Pre-clinical Research Meetings Meetings are for the purpose of reaching agreements on the design and size of clinical study for effectiveness claim Special Protocol, Pharm/Tox Only on the pharm/tox portion Special protocol, Chemistry Only on the chemistry portion Special Protocol, Medical Only for the medical portion Feldman 13 Nov 2007

Pre-IND Meeting - 1 CDER needs data that the drug is reasonably safe for use in initial small-scale clinical studies The sponsor would request a meeting with the appropriate review division. Discussions will include animal protocols, clinical testing phases, data requirements, and scientific issues needing resolution prior to clinical studies Feldman 13 Nov 2007

Pre-IND Meeting - 2 Chemistry, Manufacturing and Controls (CMC) Pre-IND meeting may be part of clinical meeting or separate Guidance document applies to both drugs and therapeutic biologics http://www.fda.gov/cdr/guidance/3683fnl.htm Topics covered in the meeting depend on what Phase study is being conducted Purpose: discuss CMC issues as they relate to the safety of the new drug/biologic for the proposed indication Feldman 13 Nov 2007

End of Phase 1 Sponsor may request a meeting after completion of Phase 1 Purpose is to review results and reach agreement on plans for Phase 2 program Feldman 13 Nov 2007

End of Phase 2/Pre-Phase 3 Meeting Primary purpose: to determine if it is safe to proceed to Phase 3. Secondary purpose: to plan the protocol for the Phase 3 study, e.g., the objectives, study design Also, to discuss and identify any additional information that may be required to support a NDA. Feldman 13 Nov 2007

Critical Path Meeting Meeting which is held to help with a stalled drug development program Purpose is to help program proceed Feldman 13 Nov 2007

Clinical Hold Meeting At any point, the CDER can impose a clinical hold, i.e., prohibit the study from proceeding or to stop a study that has started for reasons of safety, or because of a sponsor’s failure to disclose the risk of the study to the investigators. Feldman 13 Nov 2007

Pre-NDA/Pre-BLA meeting Primary purpose: to discuss the data in support of the application – filing and format issues Secondary purpose: to uncover any major unresolved problems or issues that might lead to a “refuse to file” recommendation Also, to acquaint reviewers with the information submitted and to discuss how the data will be presented in the NDA. Feldman 13 Nov 2007

90-Day Meeting Occurs 90 days after the initial submission Purpose: to discuss any issues uncovered in the first stages of the review Feldman 13 Nov 2007

Advisory Committee Meeting Purposes: To solicit outside advice and opinions from experts Recommendations are nonbinding on CDER Issues that may be discussed Opinion about a new drug Opinion about new indication for an approved drug Considerations about special regulatory requirements Advice on necessary labeling Help with proposed study Assessing if safety and efficacy data are adequate support for the NDA Feldman 13 Nov 2007

End of Review Meeting Sponsor requests meeting to determine what steps are needed to be completed by the sponsor, what additional information may be required in order for the application to be approved. Feldman 13 Nov 2007

Refusal to File Meeting The sponsor may request in writing a meeting with CDER is it refuses to file an application If, after the meeting, the sponsor wants the application, the FDA will do so under protest. Feldman 13 Nov 2007

Pre-NDA(BLA)/Supplement Meeting The purpose of this meeting is to acquaint the FDA reviewers with the general information to be submitted Discuss appropriate methods of statistical analysis Discuss proposed format for data To identify the major supporting studies Discuss any unresolved issues Feldman 13 Nov 2007

Other Possible Meetings Advertising and promotion issues Biopharm and Bioequivalence Compliance Electronic submissions Labeling Phase 4 Safety Issues Feldman 13 Nov 2007

KINDS OF MEETINGS – MEDICAL DEVICES Feldman 13 Nov 2007

Scientific/Pre-proof of Concept Testing Discuss concepts, broad outline of test plans, including need for certain bench studies, need for animal studies and need for clinical studies (no test results needed, just plans, at this meeting) Discuss regulatory options, possible pathways Discuss primary mode of action issues of a possible combination product; jurisdictional issues Feldman 13 Nov 2007

Early Collaboration Meetings http://www.fda.gov/cdrh/ode/guidance/310.html Present early prototype evaluation in preliminary animal models Discuss proposed clinical application, indication for use Get FDA feedback on bench and animal study plans; feasibility study plans. Start asking specific questions (e.g., patient population; acceptable endpoints) Discuss probable regulatory pathway (non-binding discussion), including Risk Determination for device (SR/NSR) http://www.fda.gov/cdrh/d861.html Feldman 13 Nov 2007

Pre-IDE Meeting/Post-feasibility/Pre-Pivotal Study Meeting Sponsor presents results of animal and feasibility study; describe finalized device design Sponsor discusses pivotal trial protocol (1° and 2° endpoints, duration, statistical analysis and evaluation methods), including Indication for Use and patient population FDA gives feedback on above and on proposed regulatory pathway, and nonbinding feedback on expedited status, need for Advisory Panel meeting FDA gives feedback on focused questions Feldman 13 Nov 2007

Pre-IDE Meetings Are Are Not To provide feedback on preclinical test plan To provide feedback on clinical plans Determine what is Exempt/NSR investigation To discuss international (OUS) studies Are Not A tool for negotiation For modular review To preview data For an in depth IDE review Legally binding For dispute resolution To hold FDA to years-old informal feedback To be part of a series of such meetings Feldman 13 Nov 2007

Informal Pre-IDE Meetings Not determination or agreement meetings Nothing binding May not have full review team present Individual divisions may have their own checklists about what to submit prior to the meeting – ascertain prior to sending package Feldman 13 Nov 2007

Other Device Meetings Pre-PMA Meeting 100-Day PMA Meeting Post-deficiency letter for 510(k) or PMA Appeal of final decision on PMA, 510(k), IDE disapproval Feldman 13 Nov 2007

Advisory Panel Meeting Requirements (Section 513(b)(6)(B) Must have adequate time for initial presentation Must have adequate time provided for response to any differing views by persons whose devices are the subject of a classification panel Must encourage free and open participation by all interested persons Feldman 13 Nov 2007

Advisory Panel Sponsor sends FDA material on Panel presentation FDA sends to the Sponsor the list of items it will include in package to members of the Panel FDA sends package of materials to Panel members; no new data provided within last 2 weeks prior to meeting Time lines for presentation to the Panel are provided in guidance document http://www.fda.gov/cdrh/modact/amendpan.html Feldman 13 Nov 2007

FDA Does Not Have to Accept Recommendations from the Panel Feldman 13 Nov 2007

Applies to both CDER and CBER TYPES OF MEETINGS Applies to both CDER and CBER Feldman 13 Nov 2007

Type A Is immediately necessary for a stalled drug development program to proceed Occur within 30 days of sponsor’s request Examples: Dispute resolution meetings Clinical holds Special protocol assessment after FDA evaluation Feldman 13 Nov 2007

Type B Scheduled 60 days after receipt of sponsor request Pre-IND meeting (21 CFR 312.82) Certain end of Phase 1 meetings (21CFR 312.82) End of Phase 2/Pre-Phase 3 meetings (21 CFR 312.47) Pre-NDA/BLA meetings (21 CFR 312.47) Feldman 13 Nov 2007

Type C Any meeting other than a Type A or a Type B meeting Examples of such meetings About advertising About promotional labeling Not Type C meetings – examples about launch activities and materials Postmarketing safety evaluation meetings Feldman 13 Nov 2007

Requesting a Meeting with FDA Feldman 13 Nov 2007

Whom to Meet With Check Center’s organizational chart to determine to which group to send meeting request Call the division and give a brief overview of why a meeting is being requested, i.e., the purpose and scope of the meeting; give regulatory status of the product (e.g., new, re-vamped in some way, new indication for previously approved product) Get a name of the person to whom the package should be addressed, usually the Branch Chief The package must be received before a meeting is scheduled, usually about 2-3 weeks in advance. Feldman 13 Nov 2007

Setting a date Be flexible as to dates – give several possible dates and times. NOTE: If significant additional information is submitted after the package has been sent and after the meeting has been scheduled, the meeting might be cancelled or postponed. If you have to cancel, do it at least 48 hours ahead. Feldman 13 Nov 2007

The CDER/CBER “Package” Includes: Proposed agenda; list of attendees and affiliations Product name, chemical name and structure Proposed indication(s) Dosage form, route of administration, dosing Study plans: bench, animal, clinical Summaries of prior animal or clinical data (as appropriate for phase of study) Chemistry, Manufacturing and Controls (as appropriate for Phase of study) List of objectives/outcomes expected from meeting Feldman 13 Nov 2007

The Device “Package” Includes: Proposed agenda (and time allotment) and list of attendees and each person’s affiliation Background of clinical condition or disease Currently available products, balanced view of pros and cons of each Product description and rationale for use in this condition or disease intended use and indication for us Test plans: bench, animal, clinical List of questions to be addressed at meeting Feldman 13 Nov 2007

What FDA does when it Receives the Package Branch chief receives package BC determines who will be on Review Team BC assigns project to a lead reviewer Copies prepared (or requested of Sponsor) and distributed Internal pre-meeting and sponsor meetings are scheduled Team members review package and prepare memos prior to pre-meeting Internal pre-meeting held to discuss issues, reach consensus, get further information from Team/management Feldman 13 Nov 2007

Preparing for a Meeting with FDA Feldman 13 Nov 2007

Planning the Presentation-1 Use the time optimally. Presentation of the agenda and list of attendees should take no more than 2 minutes Assume the FDA has read all of the material; do not waste time in your presentation reviewing material sent in the package. Call a week ahead of meeting to see if the Lead Reviewer can send you a list of the questions generated at their internal meeting. Feldman 13 Nov 2007

Planning the Presentation - 2 The preliminary questions from the reviewing team may cover deficiencies and/or other issues Compare your list of questions with the preliminary questions from the review team. Ensure your presentation will cover them and, if possible, without presenting significant new information. Focus your presentation to elicit as much information, comments, suggestions from the agency. Manage the time by rehearsing presenters so that they keep to their time allotment. Limit the number of presenters – too much time can be lost during change of speakers. Feldman 13 Nov 2007

Preparing for the Meeting Do a mock rehearsal with two groups of people: Those that know a lot about the product and research - to ensure you have not omitted critical information and have included all possible issues Those that do not know anything abut the product and have read only the “package” - to ensure your presentation is comprehendible and flows smoothly Feldman 13 Nov 2007

Participating in a Meeting with FDA Feldman 13 Nov 2007

The Meeting - 1 Get to the building early as there is a lengthy sign-in and inspection procedure. Meetings are usually one hour long. They will start and end on time. TURN OFF CELL PHONES AND PAGERS! There will be a sign-in sheet circulated during the meeting, which will be copied for the sponsor. Stick to the agenda. Feldman 13 Nov 2007

The Meeting - 2 Manage the time well. Leave small talk to the end, if there is time. Be brief and stay focused on scope of meeting. No side conversations. No open-ended questions. If the group gets bogged down on one issue, suggest that the one issue be handled off-line and continue with the other topics. Ensure that at least one person from your company is taking notes during the meeting. Feldman 13 Nov 2007

The Meeting - 3 While taking notes, mark the items that are action items, commitments for providing follow-up information to the company commitments for providing follow-up information to the FDA, arranging for off-line discussions Make sure there is about 10 minutes at the end of the meeting to review the Action Item list. Get a copy of the attendees list. Feldman 13 Nov 2007

Follow-Up After a Meeting with the FDA Feldman 13 Nov 2007

Debrief As soon as possible after the meeting, gather the company representatives to debrief As part of the debriefing, get people’s perceptions of the reaction to the presentation of each member of the FDA’s Team Assess if there may be any misunderstandings or mistaken impressions by anyone – can expand upon some things in the minutes or add an addendum with clarification See if you may have “supporters” Feldman 13 Nov 2007

Minutes of the Meeting Have one person take everyone’s notes and draft the minutes, including a section for the action items Distribute to the other attendees for review in order to ensure full capture of information, commitments, etc. Issue minutes to management Send to FDA with a cover letter asking for comments Feldman 13 Nov 2007

Miscellaneous Information Feldman 13 Nov 2007

References - Drugs CDER Data Standards Manual: Industry Meetings Types http://www.fda.gov/cder/dsm/drg/Drg00917.htm Formal meetings – PDUFA Products http://www.fda.gov/cder/gdlns/mtpdufa.htm Clinical Hold/Refusal to file Meetings http://www.fda.gov/cber/oversite/oversite.htm CMC IND Meetings http://www.fda/gov/cber/gdlns/ind052501.htm The New Drug Approval Process http://www.fda/gov/cder/handbook/develop.htm Feldman 13 Nov 2007

References - Devices Early Collaboration Meetings under FDAMA - Meeting guidance http://www.fda.gov/cdrh/ode/guidance/310.html Advisory Panel Meetings http://www.fda.gov/modact/amendpan.html Advisory Panel/Committee Information Contact http://fda.gov/cdrh/commline.html Feldman 13 Nov 2007