FDA releases BsUFA III Commitment Letter outlining proposed changes to biosimilar development pathway

The FDA today released a widely anticipated goals letter – also known as a commitment letter – as part of its efforts to reauthorize the Biosimilar User Fee Act (BsUFA). While the letter has been slowly negotiated between regulators and industry stakeholders since last year, today is the first time that the provisions have been made publicly available. AgencyIQ conducted a thorough review of the 36-page document to outline the key details you need to know.

Background on BsUFA

• The Biosimilar User Fee Act (BsUFA) was originally signed into law in 2012 under the FDA Safety and Innovation Act (FDASIA). Modeled off similar user fee programs for drugs and devices, BsUFA is intended to provide the FDA with the resources to hire dedicated staff and ensure a predictable, consistent review process for biosimilar products.
• As with the other user fee programs, the FDA and industry negotiate a set of “ commitments” that outline the amount of funding that industry will pay in fees in return for the FDA’s commitment to undertake certain review and policy activities. In the first reauthorization of BsUFA (known as BsUFA II, covering FY2018-2022), FDA committed to significant improvements to the program, including enhanced review transparency, a more efficient first-cycle review process, increased communication and a two-month pre-filing period for the FDA to assess an application for completeness.
• The BsUFA II agreement is set to expire in September 2022. The FDA and industry members have been negotiating in preparation for the second reauthorization of BsUFA (BsUFA III) which would begin in fiscal year 2023 and last through fiscal year 2027.

Today the FDA finally released the long-awaited text of the Commitment and Goals Letter for the BsUFA III agreement.

• AgencyIQ summarized of the 36-page document below. Among the highlights of the document: Modified meeting types, a variety of new planned guidance documents, a focus on several new regulatory science projects, efforts to bolster interchangeable products and hiring of additional FDA staff.
• Concurrently, the FDA also announced that it will soon hold a meeting to discuss the planned BsUFA activities. The meeting will take place on November 2, 2021, from 9 am to 12 pm EST.

Rethinking Resubmissions

• Core review timeline targets for original and resubmitted biosimilar product applications are set hold static at the same levels as they are under the BsUFA II agreement. The FDA will aim to review and act on 90% of original biosimilars within 10 months of the 60-day filing date, and within 6 months of receipt for any resubmissions. For manufacturing change-related supplements, the FDA aims to review applications within 4 months (for applications requiring prior approval) and “all other manufacturing supplements” within 6 months of receipt.
• However, the process now details new timelines for different types of supplemental applications: Categories A, B, C, D, E and F.
• A Category A supplement is one that the FDA defines as seeking to update the labeling for a licensed biosimilar with new safety information that has already been updated in the reference product labeling. For these submissions, the FDA would aim to take action within 3 months of the receipt of the application.
• A Category B or C supplement would take four months of FDA review. The FDA defines a Category B supplement as one seeking licensure for additional indications for which new data sets are not required and that does not seek a new route of administration or other dosage modification. A Category C supplement is one that seeks to remove an approved indication.
• A Category D supplement involves a sponsor seeking licensure for an additional indication when the application does include new data sets. The FDA would target a 6-month review period these applications.
• Category E and F supplements are the most time-intensive, taking 10 months to review following receipt (6 months for resubmissions). These are supplements seeking approval for an additional indication and containing efficacy data sets (Category E) or supplements seeking an “initial determination of interchangeability” (Category F). In addition, the FDA seeks to send so-called “filing letters” to sponsors of Category E and F supplements within 74 calendar days acknowledging receipt of the submission and detailing the planned review timeline and any substantive review issues.
• FDA’s new timelines for supplements are considerably more nuanced than previously outlined policy. In the BsUFA II agreement, the agency had agreed to review original supplements with clinical data within 10 months; resubmitted supplements with clinical data within 6 months, and manufacturing supplements within 6 months. Some companies with simpler supplements – such as those without novel clinical data sets – may find the FDA to be more responsive following these changes, even if it takes the agency a few years to start hitting its review targets as planned.
• As part of this change, the FDA has committed to releasing a guidance document (or possible a Manual of Policies and Procedures) on how companies can accurately classify supplements “for purposes of determining review timelines.” This document should be published by the end of FY2023, with final guidance expected 18 months later.

Changes to biosimilar meeting types

• Under prior BsUFA agreements, the FDA established the Biosimilar Initial Advisory (BIA) meeting. These engagements with regulators are described as an “initial assessment limited to a general discussion regarding whether licensure” as a biosimilar product “may be feasible for a particular product, and, if so, general advice on the expected content of the development program.”
• Under the new BsUFA III agreement, however, the FDA has committed to a few changes. Notably, “only one BIA meeting may be granted per program,” according to the letter.
• To best support the meetings, the FDA says “sufficient information should be provided with the meeting request to enable FDA to make such a preliminary determination related to potential licensure under section 351(k) and to provide meaningful advice.” Although this does not necessarily require the sponsor to provide preliminary comparative analytical data from a lot of the proposed biosimilar, it may include such data.
• The commitment letter provides significant detail on what should be submitted as part of these meeting requests, including the identification of the reference product, the indications intended to be sought for licensure, a comparative analytical similarity plan, a proposed bridging strategy (if warranted) and any guidance already received from other health authorities, among other information.
• The restriction to just a single BIA meeting may preserve FDA resources by requiring companies to be thoughtful about the meetings they request. However, it might also result in resources wasted elsewhere, as companies could potentially submit applications for review that would have benefitted from further, earlier engagement with regulators.
• The letter also indicates that the FDA has split the Biosimilar Product Development (BPD) Type 2 meetings – used to discuss specific issues – into two types. Under BsUFA III, there will be a Type 2a meeting and a Type 2b meeting. The former will be used to discuss a narrow group of issues following a BIA meeting or another type of BPD meeting (Type 1 is for stalled development programs; Type 3 is an in-depth data review and advice meeting; Type 4 is a pre-submission meeting).
• For example, Type 2a meetings might be used to generate feedback on revised study designs, immunogenicity testing strategies or defined CMC post-approval commitments.
• Type 2b meetings, however, are used to discuss a specific issue like proposed study designs, proposed endpoints or review of summary data. These meeting types would not include reviews of full study reports.
• Type 2a and 2b meetings will still have the same FDA target response time of 21 days – the same as the old Type 2 meetings. The meetings, which the FDA aims to hold within 60 days (for Type 2a) or 90 days (for Type 2b) may take place either in person or through a written request.
• The letter also advises that a background package “must be submitted at the same time as the written request” for the BPD or BIA meeting. FDA also plans release a revised draft guidance on the new meeting types by FY2024. In follow-up to a meeting the sponsor may submit clarifying questions to the FDA, such as to confirm something in the meeting minutes, but the FDA maintains discretion about which questions are “in-scope” for a meeting follow-up request.

Inspections

• The commitment letter calls for a range of changes to how biosimilar inspections take place. One critical type of inspection is called a Pre-Licensure Inspection (PLI) and is used to inspect a manufacturing facility before a new biosimilar is approved. Per the BsUFA III goals letter, the FDA indicated that if such an inspection is necessary the agency will aim inspect the facility “at least 60 days in advance of the pre-license inspection and no later than mid-cycle.” However, the agency said it “reserves the right” to conduct such inspections “at any time during the review cycle.”
• Alternative tools to assess manufacturing facilities: During the pandemic, the FDA experienced a host of issues with inspecting regulated facilities due to travel and personnel restrictions. Instead, it leveraged existing authority to use record requests and mutual recognition agreements with foreign regulators to conduct (admittedly limited) inspections. In the BsUFA III goals letter, the agency outlines its plan to learn from its experience during the pandemic and think about “the use of such methods beyond the pandemic.” This language is almost identical to language included in the PDUFA VII commitment letter posted earlier this month.
• As part of this effort, FDA would issue draft guidance by September 30, 2023 “on the use of alternative tools to assess manufacturing facilities named in pending applications.” This guidance would include information about “requesting existing inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements, requesting information from applicants, requesting records and other information directly from facilities and other inspected entities, and, as appropriate, utilizing new or existing technology platforms to assess manufacturing facilities.”

Advancing interchangeable

• To date, there has only been a single interchangeable product approved by the FDA, reflecting the profound challenges faced by companies developing these biological products.
• To help support the development of additional interchangeable biosimilar biological products (as the FDA calls them), the letter calls for a series of targeted investments. For example, the FDA is set to “leverage the BsUFA III Regulatory Science Program to advance product development, assist regulatory decision-making, and support guidance development for interchangeable biosimilar products.”
• Regulatory science investments will include a demonstration project meant to “investigate and evaluate the data and information (including Real World Evidence) needed to meet safety standards” for biosimilarity. For example, the FDA wants to know how to best assess and evaluate “the impact of potential differences” between the reference product and a proposed interchangeable product, as well as methodologies to predict immunogenicity issues. A second demonstration project will seek to “advance the efficiency of biosimilar product development, enhance regulatory decisionmaking based on the latest scientific knowledge, and advance the use of innovative scientific methodologies and experience with biosimilars.”
• FDA said that its regulatory science projects will then be turned into a “comprehensive strategy document” that will outline “specific actions the agency will take to facilitate the development of biosimilar and interchangeable biological products.”
• The FDA is then set to develop a series of guidance documents that could eventually help companies with development. However, many of the documents aren’t targeted for release until 2024 or later. In the letter, the FDA outlines plans for a guidance on container closure systems and device constituent parts for proposed interchangeables (September 2025); guidance on promotional labeling and advertising considerations for interchangeables (September 2024); guidance on the “nature and type of information… to support post-approval manufacturing changes to approved biosimilar and interchangeable” products (September 2024); and guidance on labeling for interchangeables (September 2023).
• While the guidance documents should prove helpful, the lengthy development time means that these answers will continue to be unavailable for years. The target publication dates are just commitments for draft guidance. The FDA will then have an additional 18 months beyond that date to finalize the guidance.

Other Proposals Outlined in the Letter

• FDA wants to promote best practices for communicating between the agency and sponsors during the review process. According to the letter, “efforts from both industry and FDA are needed in order to continue advancement, improvement, and updating of best practices.” Here, the FDA plans to update multiple guidance documents, Manuals of Policies and Procedures (MAPPs) and Standard Operating Procedures and Policies (SOPPs) by the end of calendar year 2023. These updates will consider input from an ongoing assessment of the BsUFA II process.
• The letter outlines review procedures for Use-Related Risk Analysis (URRA). Based on an URRA, a sponsor can ask the FDA to determine that a human factors validation study isn’t needed for drug-led combination products. The URRA process will involve a request from the sponsor related to the IND, which should contain scientific justifications and supporting information. The FDA then has 60 days to make a determination. According to the goal letter, the FDA plans to publish draft guidance by 2024 related to the URRA process and how it can inform decision-making. If a human factors (HF) validation study is needed, the sponsor would need to submit the protocol to the IND with specific questions. The FDA would then offer a written response within 60 days. This language is also nearly identical to language contained within the PDUFA VII commitment letter. [Read AgencyIQ’s analysis of the PDUFA VII commitment letter here.]
• Modernizing the electronic submission gateway (ESG): The FDA has committed to continuing to “ensure the usability and improvement of the ESG,” which is used to accept applications for review. The FDA is working to move the ESG to the cloud by FY2026, as described in the PDUFA VII commitment letter.
• Additional hiring: The FDA plans to hire an additional 15 full time employees (FTEs) as part of the BsUFA III program, including 14 hires in FY2023 and one additional hire in FY2024. The agency is also set to work on a report to conduct a “targeted assessment of the hiring and retention of staff for the biosimilar biological product review program.” A similar assessment was conducted during the last BsUFA agreement.
• Reducing carry-over balances: The letter says that the FDA is “committed to reducing the carryover balance” – that is, the amount of fees that the FDA has collected but not yet spent on program-related purposes – “to no greater than 21 weeks of the target revenue by the end of FY2025.”

To contact the authors of this analysis, please email Alec Gaffney ([email protected]) or Kedest Tadesse ([email protected]).
To contact the editor of this piece, please email Laura DiAngelo ([email protected])

Key Documents and Dates

BsUFA III Commitment Letter