Breakthrough Therapy (BT) Designation and Regenerative Medical Advanced Therapy (RMAT) Designation are two of the expedited programs that may apply to cellular and gene therapy products that are intended to treat, modify, reverse, or cure a serious condition. Refer to Guidance for industry Expedited Programs for Serious Conditions - Drugs and Biologics , Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance for Industry, and SOPP 8212: Management of Breakthrough Therapy-Designated Products: Sponsor Interactions and Status Assessment Including Rescinding for more information on BT and RMAT designation criteria and other expedited programs.
OTP recommends that sponsors of regenerative medicine therapies engage in discussions with OTP review staff early during product development. In particular, the Type B meetings described, including the pre-IND, end-of-phase and pre-BLA meetings, represent critical points in product development.
With regard to the number of meetings associated with RMAT or BT designation, products that receive both designations are treated as having a single designation. For example, a product that receives both RMAT and BT designation will be granted only one Initial Comprehensive Meeting.
RMAT/BT –Initial Comprehensive Meeting (Type B)
After a product receives BT or RMAT designation, sponsors are encouraged to request an “Initial Comprehensive Meeting”, which is a multidisciplinary comprehensive discussion of the drug development program, including planned clinical trials and plans for expediting the manufacturing development strategy. OTP will attempt to honor the requested format. If another milestone meeting is pending at the time that a product receives BT or RMAT designation, OTP may suggest combining the Initial Comprehensive Meeting with the milestone meeting. If a product receives BT or RMAT designation late in product development, particularly after a pre-BLA meeting has been held, an Initial Comprehensive Meeting is not necessary. Refer to SOPP 8212: Management of Breakthrough Therapy-Designated Products: Sponsor Interactions and Status Assessment Including Rescinding Appendix A on Initial Comprehensive Meeting.
Submission of Initial Comprehensive Meeting (Type B) requests to OTP
The sponsor should submit the meeting request as an amendment to the existing IND. The meeting request should include a list of the specific objectives of the meeting and a list of questions [grouped by discipline; e.g., Chemistry, Manufacturing, and Controls (CMC), pharmacology / toxicology, clinical, statistical].
Courtesy emails to the Regulatory Project Manager (RPM) for the IND and to OTPRPMS@fda.hhs.gov regarding submission of the meeting request to the file is greatly appreciated.
OTP does not send an acknowledgement email or letter following OTP’s receipt of a meeting request. However, by the timelines described in Table 5, OTP will send the decision to grant or deny the meeting request, along with the meeting date, if granted, or reasons for denial.
OTP Response to Meeting Request**
Meeting Scheduling or WRO issued***
Meeting package due to OTP
At least 30 days before the scheduled date of the meeting or WRO
OTP Preliminary Response to questions in the package to Sponsor (for teleconferences and face-to-face meetings)
NLT* 2 days before the meeting
Sponsor’s Response to FDA preliminary response (for teleconferences and face-to-face meetings)
NLT than 24 hours before the meeting
*NLT – No Later Than
Source: Table 5 information from the Formal Meetings Between the FDA & Sponsors or Applicants of PDUFA Products Guidance for Industry
**Calendar days from FDA receipt of the meeting request to the date that OTP will respond with the decision to grant or deny the meeting, as well as specifying the format and date of the meeting, if granted.
*** Calendar days from FDA receipt of the meeting request to date the meeting will be held, or the WRO will be issued.
Number of questions
The sponsor’s meeting package should include a limited number of clearly worded and targeted questions that directly address concerns about the drug development programs. The number of questions in a meeting package should not exceed what can be reasonably discussed within the duration of the allotted meeting time. For a 60-minute meeting, a maximum of 12 questions (inclusive of sub-questions) would be considered reasonable. For example, Questions 1a, 1b, 1c, 1d, 2, and 3 would be 6 questions.
Size of meeting package
It is important to include background information sufficient to support the questions in the package. OTP may cancel a meeting if the meeting package is grossly inadequate and does not contain sufficient information to enable FDA to address the questions. However, voluminous meeting packages are discouraged. Meeting packages are typically 50 – 100 pages. OTP will not commit to reviewing packages greater than 250-300 pages or answering questions that require review of this much material.
Timing of meeting package submission
Sponsors should follow the timelines for meeting package submission, as described in the Formal Meetings Between the FDA & Sponsors or Applicants of PDUFA Products Guidance for Industry and indicated above in Table 5. OTP will state the date a meeting package is to be submitted in the meeting confirmation notice when the meeting is granted.
Prior to the sponsor meeting
- OTP will send the preliminary response according to the timeline indicated above in Table 5.
- The sponsor is expected to respond to OTP’s preliminary responses according to the timeline indicated above in Table 5.
- If the sponsor finds that OTP’s preliminary responses and advice are sufficiently clear and complete to obviate the need for further discussion, the sponsor should inform OTP in writing as soon as possible so that OTP may cancel the meeting. These responses would then become the official OTP responses to the sponsor’s questions.
- If, after cancellation of the meeting, the sponsor subsequently wishes to follow-up on topics from the preliminary responses or pose new questions, then the sponsor should submit these follow-up or new questions as an IND amendment.
- If the sponsor wishes to continue with the meeting, the sponsor should identify which of the original questions in the briefing package they wish to discuss and list the questions in the proposed order of discussion. As a general rule, the order of discussion is usually the order of importance to the sponsor. When referencing questions, the sponsor should use OTP’s preliminary responses document numbering format.
- After receiving OTP’s preliminary response, the sponsor should not submit new questions and new information (e.g., alternative approaches or new proposals to address OTP comments) that were not previously submitted in the original briefing package. OTP preliminary responses are prepared after deliberative review, and usually include cross‑discipline internal discussion, of the original meeting package and questions. OTP will not have adequate time to review new material and have sufficient inter-discipline internal discussion necessary to prepare answers to new questions. Therefore, sponsors should thoughtfully prepare their meeting package and questions.
- In some situations, a sponsor may want to develop new questions/alternative approaches in response to OTP’s preliminary responses or discussion at the meeting. Such new questions/alternative approaches should be submitted as an amendment to the sponsor’s existing IND.
During the meeting
The meeting is the sponsor’s opportunity to obtain clarifications on OTP preliminary responses. As stated above, during the meeting the OTP team will not be able to provide feedback on new information (e.g., new question, alternative approaches or new proposals to address OTP comments) that was not previously submitted in the original briefing package.
Sponsors may choose to make a presentation at the beginning of the meeting. However, because OTP staff will be familiar with the meeting package content and questions, OTP recommends that sponsors forgo a presentation and use the allotted meeting time to obtain clarifications to OTP’s preliminary responses to the sponsor’s questions.
OTP recommends that time be reserved at the end of the meeting for the sponsor to summarize the major discussion points and action items.
OTP will issue meeting minutes within 30 calendar days after the meeting. OTP’s version of the meeting minutes is official and the final record of the meeting. OTP minutes are not a meeting transcript, but focus on any clarifications (e.g., of unclear preliminary responses), agreements and disagreements, and action items as discussed during the meeting.
The sponsor may submit their version of the minutes to the file to summarize their understanding of issues discussed at the meeting. However, OTP may not review such submissions; therefore, the absence of an OTP response to such submissions does not imply OTP concurrence with the sponsor’s version of the minutes.
If sponsors disagree with the content of OTP’s minutes, OTP’s meeting minutes will not be altered except to correct a substantive mistake for the record (on extremely rare occasions).
Request for Clarification
To ensure the sponsor’s understanding of OTP feedback from meeting discussions or a WRO, sponsors may submit clarification questions to the Regulatory Project Manager (RPM) within 20 calendar days following receipt of meeting minutes or a WRO. OTP will consider the request for clarification, and if determined to be limited to a clarifying nature (i.e., to confirm something in minutes or a WRO issued by OTP, rather than raising new issues or new proposals), OTP will issue a response in writing within 20 calendar days after receipt of the clarifying questions. OTP’s response will reference the original meeting minutes or WRO.
RMAT/BT – End of Phase and Pre-BLA (Type B) Meetings
OTP will grant these milestone meetings if, upon evaluation, the stage of development matches the requested milestone. Please refer to the specific milestone meetings, e.g., EOP, pre-BLA, described elsewhere on the website. Only one meeting will be granted per milestone (e.g., one EOP2). Milestone meetings should be multidisciplinary. OTP will not grant separate “clinical” and “CMC” EOP mtgs. Refer to the milestone meeting section above.
OTP will attempt to honor the requested format.
RMAT/BT – Non-Milestone Meetings
Milestone and non-milestone meetings for products with RMAT or BT designation, are scheduled as Type B (see Table 5 above). If the sponsor proposes several discipline-specific meetings within one year, OTP recommends that the sponsor consolidate the number of these meetings by combining topics and also consider if some of the information can be submitted as an amendment to the IND for informal feedback, as opposed to a formal meeting request.