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FDA Official Addresses Unanswered Questions About Interchangeable Biosimilars


Sarah Yim, MD, provided a point-by-point overview of the FDA's efforts to clarify the role of the interchangeable biosimilar designation, improve communication with manufacturers, and pay for biosimilar regulatory reviews.

With the COVID-19 pandemic more under control and the FDA settling back into its normal routines, the federal agency has had more to say lately about its efforts to develop the biosimilar market and usher more of these drugs to market.

At the GRx+Biosims 2021 meeting of the Association for Accessible Medicines this week, multiple FDA representatives, including Acting Commissioner Janet Woodcock, MD, delivered addresses intended to update the biosimilar development community on the FDA’s efforts to work the bugs out of the biosimilar development review process.

This included a talk by Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA’s Center for Drug Evaluation and Research, who focused on efforts to clarify how the interchangeable designation will be applied and how the FDA is improving manufacturer communication and timelines for biosimilar application review processes.

Interchangeability is granted for biosimilars whose developers have completed patient-switching studies involving multiple changes from reference product to biosimilar and back again. In the patient sense, it means that their pharmacist can give them the biosimilar instead of the reference brand without having to consult with the physician.

But in the manufacturing and policy community, questions have arisen that focus on whether interchangeability will apply across reference product indications and what happens if the method of biosimilar administration evolves, such as from prefilled syringe to wearable applicator, or if something changes with the reference product. Answers to these questions were not spelled out in the FDA’s original guidance on interchangeables.

“We’re going to do some things to help advance the development of interchangeable biosimilar biological products,” Yim said at GRx+Biosims. This will include development of a supportive regulatory science program and issuance of “foundational guidelines on container closure systems and device constituent parts for proposed interchangeable combination products,” she said.

Additional product support will involve development of guidelines for the labeling of interchangeable products, promotional labeling, and advertising considerations. Also in the works is guidance on supporting “postapproval manufacturing changes for different reporting categories for interchangeables,” Yim said.

“With this, we’re also going to be shooting for doing a scientific workshop on developing interchangeable products no later than October 2025,” she added.

In her presentation, Yim provided a brief timeline of recent biosimilar-related activities of significance to the commercial development sector:

  • In November 2020, the FDA initiated renegotiations for biosimilar user fee amendments (BsUFA), which was meant to insure that FDA fees charged of manufacturers for reviewing biosimilar approval applications are sufficient to pay for the work involved.
  • In December 2020, the Biologic Product Patent Transparency Act was signed into law as part of the Consolidated Appropriations Act, and this required the listing of patent information in the FDA’s Purple Book, which the biosimilar legal community has said makes the information available to biologics license applicants (biosimilar developers) much more useful.
  • In January 2021, the FDA initiated an interim assessment of the BsUFA program to evaluate biosimilar application review performance under Section 351(k) of the Public Health Service Act.
  • In April 2021, Congress passed the Advancing Education on Biosimilars Act, which called upon the FDA to continue with efforts to promote and support the use of biosimilars through a public education program.
  • In June 2021, the FDA was able to complete the BsUFA user fee negotiations and the patent information inclusion requirement for the Purple Book became effective.
  • In July 2021, the FDA approved the first interchangeable biosimilar,which happened to be the first insulin biosimilar (insuline glargine, Semglee).
  • In September 2021, the FDA published fresh guidance for biosimilar developers, approved the first ophthalmology biosimilar (ranibizumab, Byooviz), and conducted a workshop on pharmacodynamic biomarkers for biosimilar development and approval.

With regard to the Purple Book enhancements, one of the chief improvements FDA officials touted at GRx+Biosims was the inclusion of a search engine function, Yim said. The book is now fully electronic and provides information on biosimilars that are on the market. Not only is it searchable, but data also can be sorted by fields selected by the user, FDA officials have said.

"Google Biosimilars"

Yim also noted that FDA biosimilar educational materials have been improved. “If you Google 'biosimilars,' you can actually bring up a link to our landing page, and this is full of additional links to take you to additional resources.”

These resources include calendar listings of upcoming events the FDA is organizing or participating in. “This year we have more than 2 dozen events with different stakeholders, ranging from health care professionals, patient groups, payers, health care policymakers, developers, and academics. In fact, being virtual probably made it a little easier for us to attend these different meeting events,” she said.

The FDA also has plans for provider and patient videos and a modular curriculum for health care professional development.

Sarah Yim, MD

There’s a lot of changes coming up next, and we’re looking forward to continuing to work with stakeholders in terms of education, outreach, and regulatory science, as well as advancing the development of interchangeable rules.

As part of the BsUFA reviews, the FDA worked to establish timelines for labeling change approvals. These include safety information updates, added indications, and indication removals or deletions. Also, for meetings with developers that are narrowly focused on just a few key application elements, the FDA shortened the timelines for conducting these, providing a 60-day window.

The FDA also decided to reduce the background data, or “preliminary comparative analytical data,” that biosimilar applicants must bring to these meetings. “We’re also working on promoting best practices in communication during application reviews,” Yim said.

She said the FDA also is working toward issuing draft guidance on the use of alternative tools for factory inspections. Alternative tools would include means of reviewing manufacturer worthiness and quality preparations in lieu of actual site inspections, many of which were suspended during the COVID-19 pandemic because of potential COVID-19 exposure risk. 

With the start of BsUFA III in 2023, the FDA will initiate demonstration projects, one of which will advance the development of interchangeable products and another that will address the efficiency of biosimilar product development. “The details of how these are going to be operated, operationalized, and implemented are still being worked out, but we hope to have everything up and running by the start [in 2023],” Yim said.

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