BioRationality: FDA Changes the BsUFA Meetings Scope—How to Expedite the Regulatory Approval of Biosimilars

The Biosimilar User Fee Amendments of 2022 (BsUFA III) authorizes the FDA to assess and collect fees for biosimilar biological products from October 2022 through September 2027. The FDA dedicates these fees to expediting the process for the review of biosimilar biological product applications, including post-market safety activities.

In addition, it facilitates the development of safe and effective biosimilar products for the American public; this includes the FDA awarding grants for developing scientific tools and engaging in meetings with biosimilar developers to expedite the development process.

On March 3, 2023, FDA issued the 11th revision of Standard Operating Policy and Procedure (SOPP) 8101.1: Regulatory Meetings with Sponsors and Applicants for Drugs and Biological Products that instructs the FDA personnel on the operation of meetings with several significant changes that will eventually appear in the official guidance.

The FDA is updating our formal meetings guidance documents to reflect these changes, and since the FDA inter SOPP is not generally accessed by the developers, the analysis presented here should prove useful, particularly the advice on making the best use of these meetings to expedite regulatory approval.

1. This update clarifies that a face-to-face (FTF) meeting “includes in-person and virtual meetings on IT platforms that allow for audio and visual communication.” In other words, an FTF meeting between the FDA and the industry is in-person or virtual with cameras on. For now, the FDA will restrict physical FTF to Biological Product Development (BPD) Type 1 meetings only. I foresee in the future that all meetings will comply with this new definition of FTF. "Face" now means in the flesh or in front of a camera flash.
2. The Biosimilars Initial Advisory (BIA) meeting guidance states that "preliminary comparative analytical similarity data from at least one lot of the proposed biosimilar or interchangeable products compared to the U.S.-licensed reference product should be provided in the meeting package. The analytical similarity data should be sufficient to enable the FDA to make a preliminary determination as to whether licensure under section 351(k) of the 83 Public Health Service (PHS) Act may be feasible for a particular product and to provide meaningful advice." This instruction is now removed from the BIA meeting focus. Now developers can meet with the FDA before they start any work on developing a new biosimilar. This change will have 2 impacts.
   1. First, the FDA will be inundated with meeting requests as this is a free meeting, and the applicants will include future developers rather than those currently developing biosimilars. While the BsUFA fixes the time FDA takes to call in the meeting, I foresee many delays in arranging these meetings. The FDA may even amend the guidance to remove the time limit for holding the meeting.
   2. The second and most critical impact is a change in the focus of the meeting to examine a proposed development plan. However, I recommend that the FDA create such monographs, either directly or by letting the United States Pharmacopeia (USP) create these, to remove much uncertainty about what is required for developing biosimilars. This is not the same as monographs for biosimilars; the FDA has forbidden the USP from developing monographs for biological drugs due to the possibility of the reference product methods entering the protocol that might have IP protection. The development monographs should emphasize that the critical quality attributes of the release specification should not be included in the analytical assessment as currently required, such as protein content, potency, aggregates, impurities, glycan profile, isomers, etc. Essentially calling that what is good enough for patients should be good enough for the FDA. This distinction will significantly reduce the cost of development.

• A BPD Type 2 meeting is a meeting to discuss a specific issue (e.g., ranking of quality attributes; chemistry, manufacturing, and controls such as control strategy; study design or endpoints; post-approval changes) or questions for which the FDA will provide targeted advice regarding an ongoing development program. This meeting type may include a substantive review of summary data but does not include a review of full study reports." Now the Type 2 meeting is divided into 2 separate meetings (Type 2a and Type 2b) to provide more granularity to this meeting after the developer has enrolled in the program by paying a yearly fee. Classifying the types was required because, in the old Type 2 meetings, the FDA would have dozens of representatives to respond to any question that may arise. Now, it will be more focused, reducing the FDA resource requirement, but it will also help the developers to stay focused. Since these meetings are free, several meetings can be held after the enrollment fee payment. Type 2a can only be held after at least 1 previous meeting has occurred. However, calling multiple meetings with the FDA is not advised, as it slows down the pace of development.
  • BPD Type 2a Meeting: A meeting focused on a narrow set of issues (eg, often 1 but not more than 2 issues and associated questions), requiring input from no more than 3 disciplines or review divisions. Note: To request a Type 2a meeting, sponsors must first have had a BIA or other BPD meeting with the Agency.
  • BPD Type 2b Meeting: A meeting to discuss a specific issue (eg, proposed study design or endpoints) or questions where FDA will provide targeted advice regarding an ongoing biosimilar biological product development program. Note: Such a term may include a substantive review of summary data but does not include a review of full study reports.
• A BPD Type 3 meeting is an in-depth data review and advice meeting regarding an ongoing development program. This meeting type includes a substantive review of full study reports or an extensive data package (eg, detailed and robust analytical similarity data), FDA advice regarding the similarity between the proposed biosimilar or interchangeable product and the reference product based on a comprehensive data package, and the FDA advice regarding the need for additional studies, including design and analysis, based on a comprehensive data package.
  • The scope of this meeting remains the same. However, it is important to conclude that this is the first and only time when the developer can secure waivers from additional clinical studies in patients or healthy subjects. Most developers assume that the statement, "As a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human pharmacokinetic and pharmacodynamic data, and clinical immunogenicity assessment. A sponsor should provide a scientific justification if it believes that a comparative clinical study is not necessary." The only place where testing in patients is required in the Biologics Price Competition and Innovation Act is for interchangeability status. This is the time for the developers to ask the FDA this pivotal question: "Does the Agency recognize any residual uncertainty, and if so, can this uncertainty be removed by testing in patients?" This is the best approach to avoid efficacy testing in patients because the developer should always be able to demonstrate that no uncertainty can be removed by any testing in patients.^[1]
• A BPD Type 4 Meeting is a pre-submission meeting to discuss the format and content of a complete application for an original biosimilar biological product application under the Program or supplement submitted under 351(k) of the PHS Act. This meeting is mostly a format check, and most developers with experience in submitting biologic license applications will not need this meeting, cutting down the submission by at least 6 months. I strongly urge developers to seek third-party reviews before submission, regardless of their regulatory team's confidence.

Reference

[1] Niazi S. Scientific rationale for waiving clinical efficacy testing of biosimilars. Drug Des Devel Ther. 2022;16:2803-2815. doi:10.2147/DDDT.S378813