Introduction
As part of our series on formal FDA meetings, we have created this blog to help sponsors in preparing for formal meetings with the FDA to discuss their upcoming new drug application (NDA) or biologic license application (BLA) following the completion of related pivotal clinical studies. Pre-NDA/-BLA meetings are categorized as Type B meetings by the FDA and intended to occur prior to the submission of NDAs or BLAs. This blog complements the mentioned blog series, Navigating Formal FDA Meetings: Optimizing Drug Development | Inroads to Approval Series | Allucent, by discussing the purpose of Pre-NDA and -BLA meetings (21 CFR 312.47), providing approaches to create effective FDA meeting requests and packages, suggesting relevant topics to discuss at these meetings, and sharing key insights gained by former regulators and industry experts at Allucent.
Objectives of the Pre-NDA or Pre-BLA Meeting
The pre-NDA or -BLA meeting offers an opportunity to address any unresolved topics from prior development activities and to obtain final alignment with FDA regarding the strategy for preparing the content and submitting the NDA or BLA. The discussion topics must be tailored to position a sponsor to obtain the necessary information from the FDA that is crucial for supporting a successful NDA or BLA submission and approval.
Crafting Effective FDA Meeting Requests and Packages
A sponsor’s meeting documents, prepared before the meeting, can have a profound impact on the quality of feedback obtained from the FDA in the pre-NDA and -BLA meetings. This starts with the meeting request, a compilation of information deemed necessary for the FDA to evaluate the meeting’s potential value. This includes the meeting’s purpose and objectives, draft questions the sponsor wishes to ask, and the administrative details required to schedule the meeting.
Once the FDA grants the meeting, the sponsor must prepare documentation for the meeting package, submitted approximately 30 days before the meeting date. This package not only reiterates some information from the meeting request documents but also includes additional details, such as:
- Sponsor’s positions to the proposed questions
- All necessary comprehensive background information to position the FDA to provide substantive responses
- Key scientific data
- Scientifically-based justifications
- Other supporting information for the sponsor’s submissions plans for either marketing approval (NDA) or licensure (BLA).
To encourage the receipt of informative guidance and feedback from the FDA, consider the following suggestions when preparing your meeting request and meeting package:
Questions should be phrased to be unambiguous but also allow for scientific and collaborative exchange.
Questions to FDA should be written so that they promote decisive and unambiguous responses while also allowing FDA an opportunity to provide additional feedback and context that can promote discussion. In general, it is best to present a plan or process to the FDA and to solicit feedback on the proposal. Open-ended questions can lead to broad, non-specific replies that may not address the sponsor’s concerns, especially if the relevant context is not provided by the sponsor. However, direct questions, such as if the marketing applications will be approved, may also be unproductive by leading to a reply that these are “review decisions.” Careful attention should be paid to the wording and structure of each question to give sponsors the best opportunity of receiving the guidance and clarity needed to move forward.
Meeting packages should be comprehensive but have a clear intent and structure.
It is important that the meeting package contains all information pertinent to understanding the sponsor’s positioning on meeting topics and provides the basis for those positions. However, data dumping should be avoided. Instead, design and organize the package strategically so that key messages are easy to follow, and the locations of supporting information are easy to find. If the meeting package lacks adequate supporting information or if the content is poorly presented, the Reviewer may not fully understand the sponsor’s viewpoint and the value of feedback could be limited. Sponsors are encouraged to take control of the messaging and to direct it, rather than leaving the FDA to draw its conclusions without understanding the basis of the Sponsor’s position(s).
Timelines should be carefully reviewed prior to requesting a meeting.
Once a meeting request is submitted, timelines are no longer under the sponsor’s control. Failing to deliver the meeting package by the date designated in the meeting granted letter may result in delays or cancelation of the meeting. To avoid such setbacks, meeting requests should only be submitted when the sponsor is confident that the meeting package and its contents can be completed within the limited time frame. The meeting package should be complete enough to ensure that the questions to the FDA and related content in the meeting request provide a clear perspective on the program challenges and approaches to mitigate them, as well as the insights needed from the FDA. The meeting request should be written to provide a clear picture of the sponsor’s needs and the urgency for addressing each, which should enable the FDA to adequately prepare for the meeting.
Topics to Discuss in the Pre-NDA Meeting
The specific questions raised to the FDA in the pre-NDA and -BLA meetings can vary wildly depending on the product, indication, development history, and a variety of other factors. Though discussion topics will need to be customized to fit the particular needs of the planned application, there are trends in the types of information that should be addressed. Below is a series of example topics that may be helpful to consider when requesting your pre-NDA and -BLA meetings.
The structure and components for the application
Regulatory strategy considerations for the structure, composition, or approach for the application are critical as they impact how the history of the program is organized and presented. For example, the integration of safety/efficacy summaries may be complicated if the conditions for data collection preclude comparisons. This may result in certain Modules or Sections being omitted from the application and require FDA feedback. Across this and other scenarios, FDA agreement on submission of any minor components may be requested during the Filing Review period, which occurs within the first 60 days from NDA/BLA submission.
General examples of content in which there may be a need to ask questions about formatting and structure include:
- Final study reports and data sets, such as legacy format
- Real-world evidence
- Late-breaking results
- Estimated date(s) for submission of audited draft and final reports.
The use of clinical findings from pivotal studies and other supporting evidence
- The use of patient data obtained outside of the United States, including the scientifically based justification to support using these findings.
- Available efficacy data that support the proposed indication, including how primary endpoints in pivotal studies were defined and related statistical analyses. Note that the FDA will withhold specific decisions on product labeling; this will be determined during review of the application.
- Plans for clinical safety activities, such as the status and extent of the safety database, the timing for data from long-term follow-up, and content to be included in the 120-day safety update.
- Plans for the integrated analyses of safety and efficacy (ISS and ISE, respectively). This may also include a proposal for how publicly available data (literature articles, FAERS database) may inform the integrated summaries. A discussion on the adequacy of the design of the studies summarized and related data collected may also be included.
Nonclinical information for the to-be-marketed presentation
Nonclinical data are typically critical to support product development through the submission of the NDA or BLA in the absence of adequate clinical experience. Nonclinical issues typically discussed at pre-NDA/BLA meetings are:
- Adequacy of safety justifications (e.g., for impurity levels, maximum daily levels of excipients)
- Need for additional nonclinical testing for unexpected adverse clinical findings
- Verification that the completed and planned studies are adequate to support the planned NDA/BLA in terms of the findings to be submitted and the timing for study report submissions
Manufacture and quality information for the to-be-marketed presentation
As mentioned above, a variety of product quality issues may need to be addressed in the pre-NDA/-BLA meeting. Examples include,
- Adequacy of potency assays
- Stability data
- Commercial release specifications and assay readiness
- Compatibility and bridging of clinical study formulation to the commercial version
- Confirmation that all facilities will be ready for inspection by the time of NDA submission
- Qualitative and quantitative information for individual excipients
- Container closure description and information supporting safety
The plan and rationale for referencing another product for 505(b)(2) NDAs and biosimilar BLAs
- Both the 505(b)(2) NDA and biosimilar BLA pathways rely on a referenced product to support approval.
- The 505(b)(2) pathway is a type of NDA that allows a sponsor to rely either partially or fully on investigations that “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted” (21 U.S.C. 355(b)(2)). This support can be derived from the published literature or from FDA’s previous determinations of safety and/or effectives for an approved drug.
- Biosimilar BLAs are abridged development programs that demonstrate that the biologic being developed is comparable to the product referenced based on extensive analytical testing, followed by targeted nonclinical and clinical assessments, if warranted.
- Depending on the regulatory strategy for these applications, it’s possible for the pre-NDA/-BLA meeting to be held with only limited, or even no, prior discussions with FDA. If not done so previously, these meetings the pre-NDA/-BLA meeting provides an opportunity to gain FDA’s concurrence on the extent and type of information that will be leveraged and to obtain FDA’s feedback on the justification(s) that will support reliance on the referenced product, as well as related strategies for product development.
Unresolved issues from previous FDA meetings or other formal interactions.
Across product development programs, multiple formal meetings are typically conducted, and various issues may be identified. For example,
- product quality issues are typically identified throughout the product development life cycle due to concerns about the impurity levels, the quantity and quality of stability data, and the safety qualification of the maximum daily amount of the excipients employed in the product.
- Nonclinical testing issues may arise due to unexpected toxicities in the clinic, as well as failure to properly address the clinical relevance of toxicities observed in animal species.
- Similarly, unexpected safety issues may be observed in the clinic that warrant additional testing.
Therefore, sponsors should provide a thorough account of the regulatory history of the product, confirm how unresolved issues from previous meetings will be addressed in the NDA submission, as well as justify why continued discussion (if needed) is warranted to help resolve existing issues.
Concluding Statement
Pre-NDA or Pre-BLA meetings provide an opportunity for sponsors to engage the FDA by providing the strategy related to preparing and submitting an NDA or BLA, as well as the evidence that supports either marketing approval (NDA) or licensure (BLA) of their product. Sponsors that prepare for these meetings by following the advice above are better able to conduct proper due diligence of programs before engaging the FDA. Such due diligence helps to maximize the benefits of FDA engagement via the pre-NDA/-BLA meetings by best positioning the FDA to provide clear and helpful feedback that can be used to either confirm the adequacy of the strategy shared and evidence provided or to adjust both to ensure the submission of a successful application.