Stakeholders ask for transparency, agency rationale in FDA meeting decisions
Regulatory News | 27 August 2024 |
FDA headquarters in White Oak, MD. (Source: Ferdous Al-Faruque)
Stakeholders want more transparency and clarity on how the US Food and Drug Administration (FDA) conducts meetings with drug and biologics sponsors. They also want the agency to provide its rationale when certain aspects of their meeting requests are denied, including requests for in-person and virtual meetings.
Several industry groups, including PhRMA and the Biotechnology Innovation Organization (BIO), wrote to FDA in response to a July public meeting on best practices for conducting meetings between regulators and sponsors regarding its meeting obligations under the Prescription Drug User Fee Act (PDUFA VII). They noted that the agency has consistently missed negotiated PDUFA performance goals for key meeting management metrics, which the groups said is burdensome for companies.
BIO noted that FDA's own performance report has found that it failed to meet 9 out of 14 meeting-related commitments in FY 2022.
"Given the criticality of these interactions, this level of performance may have a deleterious impact on FDA’s and industry’s shared goals of expeditiously developing and providing novel, safe, and effective therapies for patients," said the group. "Establishing and implementing best practices for both industry and the agency would improve the planning and conduct of FDA/sponsor interactions, potentially improving performance against PDUFA goals."
PhRMA and BIO both commented on the need for in-person and virtual meetings with regulators over written response only (WRO) letters. They noted that sponsors prefer direct communication with FDA staff to get quick responses but are often denied such meetings and instead given WRO letters that slow down the process.
PhRMA pointed out that more than half of FDA-sponsor interactions are through WRO letters that allow sponsors to ask clarifying questions extemporaneously. It added that WRO communications could delay the process by 40 days or more to answer questions that could have been answered instantly during more direct meetings.
"Therefore, when FDA is seeking to convert a meeting request to a WRO, PhRMA recommends the agency provide sponsors both with the rationale for this conversion and an expedited mechanism for sponsors to appeal this decision," said PhRMA. “Moreover, additional information on the FDA Review Centers, Divisions, and disciplines who provided input into a WRO and their associated role in developing the WRO would also be useful."
Similarly, BIO also asked FDA to require its staff to provide sponsors a rationale for denying more direct meetings and instead opting for WRO letters. It asked the agency to identify which staff should be included in meetings and ensure they are prepared, and that all staff from relevant divisions be considered for participation, and sponsors be allowed to ask representatives from relevant disciplines to be included.
“If certain FDA disciplines that the sponsor requested will not participate, the FDA [regulatory program manager (RPM)] should provide an explanation and discuss with the sponsor ahead of the meeting,” said BIO. “Project managers should be transparent about workload demands and availabilities of key staff prior to granting a requested meeting and collaborate with the sponsor to identify an appropriate solution.”
“Sponsors can then make a more informed choice about whether to maintain the current meeting or seek an alternative,” the group added.
During in-person and virtual meetings, BIO recommended that FDA and sponsors agree to develop meeting minutes summarizing their discussions to confirm agreements and minimize communication discrepancies. The group said that RPMs could receive training on maintaining live meeting minutes, and technologies and tools such as artificial intelligence (AI) could be used to achieve the objective.
BIO also noted that sponsors must currently request information on the titles and functions of FDA officials and their role in the meeting, and the agency should provide that information proactively. It also highlighted the importance of clear and frequent communication between RPMs and sponsors and said FDA should establish guidelines and processes for RPMs so their interactions with sponsors are more predictable.
PhRMA echoed the sentiments and added that FDA should ensure that appropriate personnel with decision-making authority are part of meetings. It said that sponsors who receive WRO responses also get complete information on the staff members who provided input in the letters. The group said this is especially important when the agency needs cross-division or cross-discipline coordination.
"Development timelines can be significantly delayed when the agency requires sponsors to seek advice from a second division,” said PhRMA. “Seeking guidance from multiple divisions can also generate regulatory uncertainty as many sponsors have anecdotally reported receiving conflicting advice from different divisions and disciplines within FDA."
Similarly, PhRMA asked that industry and FDA adopt standard meeting management best practices such as designating an FDA representative who will ensure all sides stay on the agenda during meetings and everyone should ensure that the right people are in attendance.
"Towards this end, PhRMA requests that FDA proactively provide the current titles of all attendees, their function - for example, lead CMC reviewer - and the role they play in the meeting (e.g., decision-makers or observers)," said PhRMA. "Currently, sponsors must request this information after receiving the list of attendees or try to independently ascertain this information."
"If certain agency experts are not participating or are unable to participate, PhRMA requests the Regulatory Project Manager (RPM) provide an explanation and discuss attendance with the sponsor ahead of the meeting," the group added. "RPMs should be transparent about workload demands and availabilities of key staff prior to granting a requested meeting, so sponsors can make a more informed choice about whether to maintain the current meeting or seek an alternative."
FDA has set the maximum number of questions sponsors can ask in their meeting requests, and BIO advised that sponsors should carefully review and prioritize those questions to ensure they are productive and mitigate potential development delays.
"Briefing books should contain sufficient relevant information for FDA to respond to the questions in a meaningful way, but not contain too much information," the group added. "BIO appreciates that this is a complicated balance to strike. Additional information from FDA regarding the appropriate balance from their perspective would be helpful to Sponsors."
PhRMA noted that sponsors try to submit meeting requests as early as possible that includes their rationale for what meeting types they think are appropriate. They also include background packages that are as succinct as possible with 10 or fewer questions consistent with FDA requirements. However, the group asked the agency to clarify how good timing for meetings and good amount of detail in their questions are defined.
"This additional information will help sponsors strike the right balance for meeting packages, as sponsors report they often receive feedback from the agency that briefing books have either too much or too little information," said PhRMA.
Stakeholders commented broadly on several types of meetings, but one meeting that is of particular interest are INitial Targeted Engagement for Regulatory Advice (INTERACT) meetings under PDUFA VII that sponsors can request after they've identified an investigational product to evaluate in clinical studies but where they have not yet designed and conducted definitive toxicology studies.
While the industry has offered praise for the INTERACT meetings, BIO said that FDA's criteria for granting INTERACT meetings are unclear and applied inconsistently, which may account for its high rate of meeting denials. It noted that sponsors are uncertain about what topics and questions qualify for the meetings and when it is appropriate to request an INTERACT meeting instead of a pre-investigational new drug (pre-IND) meeting.
“Industry would benefit if FDA provided additional context as to why requests are denied and what interaction pathway(s) could be taken with FDA to obtain answers to the questions submitted instead,” said BIO. “In general, sponsors would like to reserve the opportunity to hold a pre-IND meeting until after IND-enabling studies are completed, given there is typically only one opportunity for this meeting type.”
Similarly, the group also asked for clarification on the range of topics appropriate for Type D meetings and the rationale for when a Type D meeting may be converted to a Type C meeting.
“Sponsors continue to have issues with unclear written responses that require follow-up clarification, especially when a WRO was not requested,” said BIO. “Sponsors need FDA to directly answer the specific question asked in order to keep development timelines on track.”
Stakeholder comments
Several industry groups, including PhRMA and the Biotechnology Innovation Organization (BIO), wrote to FDA in response to a July public meeting on best practices for conducting meetings between regulators and sponsors regarding its meeting obligations under the Prescription Drug User Fee Act (PDUFA VII). They noted that the agency has consistently missed negotiated PDUFA performance goals for key meeting management metrics, which the groups said is burdensome for companies.
BIO noted that FDA's own performance report has found that it failed to meet 9 out of 14 meeting-related commitments in FY 2022.
"Given the criticality of these interactions, this level of performance may have a deleterious impact on FDA’s and industry’s shared goals of expeditiously developing and providing novel, safe, and effective therapies for patients," said the group. "Establishing and implementing best practices for both industry and the agency would improve the planning and conduct of FDA/sponsor interactions, potentially improving performance against PDUFA goals."
PhRMA and BIO both commented on the need for in-person and virtual meetings with regulators over written response only (WRO) letters. They noted that sponsors prefer direct communication with FDA staff to get quick responses but are often denied such meetings and instead given WRO letters that slow down the process.
PhRMA pointed out that more than half of FDA-sponsor interactions are through WRO letters that allow sponsors to ask clarifying questions extemporaneously. It added that WRO communications could delay the process by 40 days or more to answer questions that could have been answered instantly during more direct meetings.
"Therefore, when FDA is seeking to convert a meeting request to a WRO, PhRMA recommends the agency provide sponsors both with the rationale for this conversion and an expedited mechanism for sponsors to appeal this decision," said PhRMA. “Moreover, additional information on the FDA Review Centers, Divisions, and disciplines who provided input into a WRO and their associated role in developing the WRO would also be useful."
Similarly, BIO also asked FDA to require its staff to provide sponsors a rationale for denying more direct meetings and instead opting for WRO letters. It asked the agency to identify which staff should be included in meetings and ensure they are prepared, and that all staff from relevant divisions be considered for participation, and sponsors be allowed to ask representatives from relevant disciplines to be included.
“If certain FDA disciplines that the sponsor requested will not participate, the FDA [regulatory program manager (RPM)] should provide an explanation and discuss with the sponsor ahead of the meeting,” said BIO. “Project managers should be transparent about workload demands and availabilities of key staff prior to granting a requested meeting and collaborate with the sponsor to identify an appropriate solution.”
“Sponsors can then make a more informed choice about whether to maintain the current meeting or seek an alternative,” the group added.
During in-person and virtual meetings, BIO recommended that FDA and sponsors agree to develop meeting minutes summarizing their discussions to confirm agreements and minimize communication discrepancies. The group said that RPMs could receive training on maintaining live meeting minutes, and technologies and tools such as artificial intelligence (AI) could be used to achieve the objective.
BIO also noted that sponsors must currently request information on the titles and functions of FDA officials and their role in the meeting, and the agency should provide that information proactively. It also highlighted the importance of clear and frequent communication between RPMs and sponsors and said FDA should establish guidelines and processes for RPMs so their interactions with sponsors are more predictable.
PhRMA echoed the sentiments and added that FDA should ensure that appropriate personnel with decision-making authority are part of meetings. It said that sponsors who receive WRO responses also get complete information on the staff members who provided input in the letters. The group said this is especially important when the agency needs cross-division or cross-discipline coordination.
"Development timelines can be significantly delayed when the agency requires sponsors to seek advice from a second division,” said PhRMA. “Seeking guidance from multiple divisions can also generate regulatory uncertainty as many sponsors have anecdotally reported receiving conflicting advice from different divisions and disciplines within FDA."
Similarly, PhRMA asked that industry and FDA adopt standard meeting management best practices such as designating an FDA representative who will ensure all sides stay on the agenda during meetings and everyone should ensure that the right people are in attendance.
"Towards this end, PhRMA requests that FDA proactively provide the current titles of all attendees, their function - for example, lead CMC reviewer - and the role they play in the meeting (e.g., decision-makers or observers)," said PhRMA. "Currently, sponsors must request this information after receiving the list of attendees or try to independently ascertain this information."
"If certain agency experts are not participating or are unable to participate, PhRMA requests the Regulatory Project Manager (RPM) provide an explanation and discuss attendance with the sponsor ahead of the meeting," the group added. "RPMs should be transparent about workload demands and availabilities of key staff prior to granting a requested meeting, so sponsors can make a more informed choice about whether to maintain the current meeting or seek an alternative."
FDA has set the maximum number of questions sponsors can ask in their meeting requests, and BIO advised that sponsors should carefully review and prioritize those questions to ensure they are productive and mitigate potential development delays.
"Briefing books should contain sufficient relevant information for FDA to respond to the questions in a meaningful way, but not contain too much information," the group added. "BIO appreciates that this is a complicated balance to strike. Additional information from FDA regarding the appropriate balance from their perspective would be helpful to Sponsors."
PhRMA noted that sponsors try to submit meeting requests as early as possible that includes their rationale for what meeting types they think are appropriate. They also include background packages that are as succinct as possible with 10 or fewer questions consistent with FDA requirements. However, the group asked the agency to clarify how good timing for meetings and good amount of detail in their questions are defined.
"This additional information will help sponsors strike the right balance for meeting packages, as sponsors report they often receive feedback from the agency that briefing books have either too much or too little information," said PhRMA.
Stakeholders commented broadly on several types of meetings, but one meeting that is of particular interest are INitial Targeted Engagement for Regulatory Advice (INTERACT) meetings under PDUFA VII that sponsors can request after they've identified an investigational product to evaluate in clinical studies but where they have not yet designed and conducted definitive toxicology studies.
While the industry has offered praise for the INTERACT meetings, BIO said that FDA's criteria for granting INTERACT meetings are unclear and applied inconsistently, which may account for its high rate of meeting denials. It noted that sponsors are uncertain about what topics and questions qualify for the meetings and when it is appropriate to request an INTERACT meeting instead of a pre-investigational new drug (pre-IND) meeting.
“Industry would benefit if FDA provided additional context as to why requests are denied and what interaction pathway(s) could be taken with FDA to obtain answers to the questions submitted instead,” said BIO. “In general, sponsors would like to reserve the opportunity to hold a pre-IND meeting until after IND-enabling studies are completed, given there is typically only one opportunity for this meeting type.”
Similarly, the group also asked for clarification on the range of topics appropriate for Type D meetings and the rationale for when a Type D meeting may be converted to a Type C meeting.
“Sponsors continue to have issues with unclear written responses that require follow-up clarification, especially when a WRO was not requested,” said BIO. “Sponsors need FDA to directly answer the specific question asked in order to keep development timelines on track.”
Stakeholder comments
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