FDA Guidance on Biosimilar Substitution Needs Work, Commenters Say

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By John T. Aquino

The FDA needs to clarify its standards for showing a biosimilar drug is interchangeable with the original biologic and how the biosimilar should be named and labeled, commenters said in response to an agency draft guidance.

The Food and Drug Administration draft, released Jan. 17, described how an applicant can establish that a biosimilar, a highly similar, less expensive version of an FDA-approved biologic drug, can be substituted for the biologic on which it is based without a physician’s approval. The agency extended the comment deadline to May 19 and had posted 56 comments from a wide range of respondents by May 24.

Biosimilar applicants like Sandoz Inc. are closely watching the FDA’s progress toward a final guidance on the interchangeability designation, which is likely to generate higher revenues because patients can be switched more easily to the substitute drug. Meanwhile, original biologic makers like AbbVie Inc. are interested in keeping their product exclusivity for as long as possible.

Stacie Ropka, whose practice at Axinn, Veltrop & Harkrider LLP, Hartford, Conn., focuses on biopharmaceutical patent litigation, told Bloomberg BNA in a phone interview the comments break down into certain predictable groups. “If you’re a biosimilar applicant, you’re happy the FDA has provided the guidance, but you think it’s asking for too much information,” she said. “If you’re the owner of the patent for the original biologic, you strongly support the need for the switching studies the FDA requires in order to show that switching from the original biologic to the biosimilar is safe. If you’re an organization that represents patients, you want assurances the interchangeable biosimilar is safe and effective for each condition for which the original biologic is approved.”

Ropka said she believes the FDA will proceed toward a final guidance “in a manner to ensure interchangeable biosimilar products get to the marketplace promptly but in a way that doesn’t compromise safety. In other words, in the same way the agency finalized its guidance on biosimilarity.”

Higher Standard or Not?

The Biologics Price Competition and Innovation Act (BPCIA) provides an abbreviated pathway for FDA approval of a biosimilar utilizing the data submitted to FDA for the original product, also known as the reference product (RP). Under the BPCIA, after the applicant provides additional data, the FDA can designate a biosimilar as interchangeable. The FDA has approved five biosimilars since the BPCIA became effective in 2010, but none so far has received the interchangeable designation.

Commenters disagreed whether the standard for approving biosimilarity and interchangeability should be the same or if a higher standard is needed for interchangeability.

Sandoz, a division of Novartis, and the company that developed the first biosimilar approved by the FDA under the BPCIA, wrote: “We believe it is critical that the Agency clarify that interchangeability is a requirement for additional data and does not represent a higher standard for the product itself. It is important for stakeholders across the health care industry to understand that FDA does not have more than one standard of product quality for the approval of biologics [and that] any suggestion that a biosimilar is somehow less safe and effective before it is designated as an interchangeable biologic is clearly an inappropriate conclusion since it is the very same product (molecule and formulation).”

The biopharma Pfizer similarly wrote: “The Draft Guidance should be clear that while the extent of analytical similarity will affect overall data requirements in other areas, there is not an additional analytical standard for demonstration of interchangeability.”

In contrast, Patients for Biologic Safety and Access (PBSA) stated: “While some FDA officials have indicated the interchangeability standard is different, not higher, FDA must abide by clear Congressional intent by requiring a higher standard of approval.” While under the BPCIA, a biosimilar must be highly similar to and have no clinically meaningful differences with its RP, Congress required interchangeable biosimilars be both biosimilar to an FDA-approved reference product and produce the same clinical result as the reference product in any given patient, the PBSA wrote.

The Biotechnology Innovation Organization stressed in its comments that interchangeability is a legally and scientifically distinct standard from biosimilarity and should be considered an additional standard to the threshold standard of biosimilarity. The FDA must not conflate the two, BIO argued, even though a biosimilar applicant will develop a single data package to address both biosimilarity and interchangeability.

Robust Switching Studies

The American Society of Clinical Oncology (ASCO) joined many of the commenters in asking for clarity concerning switching studies used to determine the impact of alternating or switching between the proposed interchangeable product and the RP.

In the guidance document, the ASCO stated, switching studies are required when the sponsor intends for the biological product to be administered to a patient more than once. “The draft guidance indicates that switching is a single change, whereas alternating involves repeated changes between the interchangeable product and the reference product,” ASCO noted. “However, the understanding of what will be expected of the sponsor to demonstrate either switching or alternating remains unclear in the guidance document. The explanations and expectations of switching and alternating are described in parallel, and because the result of either type of study could be a designation of interchangeable, the breadth of difference between switching and alternating should be clarified.”

The Pharmaceutical Research and Manufacturers of America (PhRMA) requested that the guidance provide further recommendations on the design of switching studies. “In particular, because PK [pharmacokinetic] and pharmacodynamic (PD) assessments [measuring the effect the body has on drugs and the effect drugs have on the body] might not capture all clinically relevant differences between a proposed interchangeable product and reference product, PhRMA believes that switching studies also generally should include a robust assessment of efficacy and the ability of the biosimilar to produce both a wanted and unwanted immune response.”

The biopharma AbbVie asked in its comments that the switching studies be made tougher than the FDA has described. "[The] FDA should revise the draft guidance to recommend that switching studies to demonstrate interchangeability provide a comparison of efficacy under more stringent margins than those used in the biosimilarity exercise and a comprehensive assessment of immunogenicity associated with repeated switching.”

Use of Non-U.S. Studies

The draft guidance said using clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is interchangeable with the RP generally wouldn’t be appropriate in a switching study. Use of the word “generally” caused disagreement among commenters over whether data from non-U.S. products should ever be used in switching studies.

The AARPwrote: “There is no scientifically justifiable reason for non-U.S. products to be acceptable for biosimilar approval but not for an interchangeability designation.”

Johnson & Johnson, however, noted the differences in versions of biologics approval in other countries are usually minor but can be more substantial. “Accepting the use of non-U.S. products for switching studies would be based on the assumption that the U.S. and non-U.S. reference product are interchangeable,” J&J wrote.

Naming, Labeling

Commenters also disagreed over whether the final guidance should require that an application for interchangeable designation demonstrate the product is interchangeable for each condition for which the reference product is approved. There was consensus that the term “fingerprint-like characterization,” which the FDA said could reduce residual uncertainty about interchangeability, wasn’t defined, was unclear, could lead to confusion, and so required clarification. There was also general agreement that interchangeability refers to the biosimilar and the RP, not the biosimilar and other biosimilars.

Those commenting also generally complained that the draft guidance didn’t discuss naming and labeling of interchangeable biosimilars, although the FDA promised to do so. Genentech, a member of the Roche Group, began its comments discussing the need for naming and labeling guidance for interchangeables, and Earl S. Dye, its director of pharma regulatory policy, reiterated this in a May 18 e-mail to Bloomberg BNA. Commenters did, however, disagree on how the products should be named.

PhRMA recommended that the non-proprietary name of an interchangeable product should be distinguished from that of the RP and other interchangeable products through a unique suffix. It also requested that biosimilar labeling state whether or not the FDA has made a determination of interchangeability with the RP and include any such FDA finding, in addition to a definition of interchangeability.

The consumer group Citizens Against Government Waste, however, wrote that it remained disappointed that the FDA didn’t decide to use the same non-proprietary name for a RP and a biosimilar and instead adopted the use of the same non-proprietary name with an attached randomly selected four-letter suffix for each originator biologic product, related biologic product, and biosimilar. “This methodology will be confusing and difficult to follow, and will discourage the use of biosimilars. The FDA should revise its guidance on this issue,” CAGW wrote.

To contact the reporter on this story: John T. Aquino in Washington at jaquino@bna.com

To contact the editor responsible for this story: Randy Kubetin at RKubetin@bna.com

For More Information

Comments to the draft guidance can be found at http://src.bna.com/pay.

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