Comments on FDA Interchangeability Draft Guidance Run the Gamut

Over the last few years, the FDA has taken multiple steps to level the playing field between biosimilars and interchangeable biosimilars. More recently, it proposed draft guidance that would do away with switching studies for interchangeability status. Commenters on that guidance were mostly supportive — with some even backing interchangeability for all biosimilars — and others asked for clarification on a range of issues, including what information the FDA needed to make a determination of interchangeability. Meanwhile, one group derided the guidance as an “ill-advised and inappropriate move.”

Based on the agency’s experience with biosimilars and interchangeable biosimilars, the FDA on June 20 published the draft guidance “Considerations in Demonstrating Interchangeability With a Reference Product: Update.” Since the initial interchangeability guidance — published on May 19, 2019 — the FDA’s “experience has shown that for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product. Accordingly, FDA’s scientific approach to when a switching study or studies may be needed to support a demonstration of interchangeability has evolved.”

The agency has gained experience in analyzing the “potential analytical differences” between proposed biosimilars and their reference drugs and how those impact clinical performance, it said. The guidance also notes that “currently available analytical technologies can structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity using in vitro biological and biochemical assays.”

Because of this, the FDA said, companies applying for the interchangeable designation may offer an assessment of why the comparative analytical and clinical data support the switching standard in the Biologics Price Competition and Innovation Act of 2009 (BPCIA). They also should include in their applications any other relevant information as far as safety and efficacy in switching between the reference drug and the biosimilar.

The FDA noted that of the 13 interchangeable biosimilars that it had approved at the time of the recent draft guidance, nine did not include data from a switching study.

A notice on the guidance was published in the Federal Register on June 21 (89 FR 52060). Its comment period ended Aug. 20, and as of mid-September, 38 comments had been posted at Regulations.gov.

Some Say Guidance Would Produce Cost Savings

Many respondents expressed their support of the FDA’s thinking on the issue.

Cardinal Health, for one, remarked that it should help boost the use of biosimilars while also promoting savings within the health care system. The distributor said it looked forward to working with the agency on the guidance “and any future policies that promote and advance biosimilar accessibility.”

The Academy of Managed Care Pharmacy (AMCP) maintained that the guidance “will alleviate much of the uncertainty and remove impediments to a competitive biosimilar marketplace. An interchangeability pathway that no longer requires switching studies for each condition of use for the reference product relieves the undue burden previously placed on biosimilars.”

The Association for Clinical Oncology (ASCO) said it supports the guidance, as did the Leukemia & Lymphoma Society. Provider-focused respondents, including the American Medical Association, the American College of Rheumatology, Vizient, Inc. and Doctors for America, also expressed support, as did Kaiser Permanente, which said it supports recognizing all biosimilars as interchangeable.

That same approach was taken by some biosimilar manufacturers, including Fresenius Kabi U.S. and Samsung Bioepis Co., Ltd. The latter company also recommended that the FDA reevaluate the exclusivity granted to the first interchangeable biosimilar of a drug, as did Arnold Ventures.

The National Council for Prescription Drug Programs (NCPDP) said it supported the draft guidance and also requested that the FDA “revisit the need for its suffix-based biosimilar naming convention.”

A handful of organizations representing payers commented, including AHIP, the Blue Cross Blue Shield Association, CVS Health, Prime Therapeutics LLC, The Cigna Group and UnitedHealth Group. All said that they were in favor of biosimilars being automatically interchangeable, with some citing the high costs of switching studies for manufacturers, and others touting the savings they had realized by using the agents. PBM advocacy group Pharmaceutical Care Management Association (PCMA) also pushed for doing away with the interchangeability designation entirely.

The Federal Trade Commission (FTC) contended that more products with interchangeable status could help with competition and uptake of biosimilars, as pharmacists would be able to substitute the agents for their reference drugs consistent with state law. This would be consistent with the BPCIA’s goals, it said. In addition, said the FTC, the approach would “reduce marketplace confusion about the safety and efficacy of interchangeable biosimilars as compared to other biologic products.”

It called for the FDA to publish additional guidance explaining how approved biosimilars without interchangeable status could request that designation. The draft guidance addresses how only biosimilars pending at the FDA could submit an amendment requesting interchangeability.

Some Respondents Raised Concerns

The FTC and some other respondents also expressed concern around manufacturers making “false and misleading” comparisons between reference products and biosimilars. For example, The Biosimilars Forum said it was “concerned that product sponsors may seek to artificially differentiate interchangeable biosimilars supported by a switching study and those that are not,” and asked that the FDA add content to the guidance explicitly saying that “approving an interchangeable biosimilar without a switching study does not compromise its safety, efficacy, or quality and suggesting otherwise would be false and misleading.”

The Biosimilars Council, a division of the Association for Accessible Medicines, cautioned that reference drug manufacturers may try to force the FDA to require a switching study before it approves an interchangeable agent by submitting a Citizen Petition or submitting the request as correspondence, the latter of which might not give the biosimilar company the opportunity to respond. It urged the FDA to reject such correspondence and instruct manufacturers to submit those concerns as 505(q) Citizen Petitions, which offer “safeguards to minimize unnecessary delays.” In addition, it said the agency should refer “any petitions submitted that it determines were submitted with the primary purpose of delaying an application” to the FTC.

Comments from three clinicians and health services researchers at the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) said they supported the FDA’s attempt to lower barriers for applicants with interchangeable products but also requested some revisions to the guidance, including more specific information on what the agency is looking for in terms of “comparative analytical and clinical data” to establish bioequivalence.

In the interest of transparency, they also asked the FDA to publish “detailed justifications of interchangeability decisions” that it has made, a move that would benefit both patients and clinicians, as well as other biosimilars sponsors. And they requested that the agency update drug labels “in a timely manner to reflect interchangeable biosimilar status”; noting that of the 15 FDA-approved interchangeable biosimilars as of July, only two — Eli Lilly and Co.’s Rezvoglar (insulin glargine-aglr) and Biocon Biologics Inc.’s Semglee (insulin glargine-yfgn — have that designation on their labels. Including that information “will increase prescriber awareness and confidence” in biosimilars, they stated.

Ultimately, the FDA should sunset the interchangeable designation, the group asserted, a sentiment expressed by other commenters, including the employer-focused ERISA Industry Committee (ERIC), which called the switching study requirement “a hurdle which delays and prevents competition.”

PhRMA, Others Request Revisions

The Pharmaceutical Research and Manufacturers of America (PhRMA) said that while it supports the BPCIA’s implementation, the draft guidance “would benefit from clarification and expansion in several respects.” For example, it called for the FDA to provide examples of what kind of information is needed to support a biosimilar being deemed interchangeable.

The advocacy group for biopharma research companies also encouraged the FDA “to revise the Draft Guidance Update to clarify that switching studies may still be necessary for some products and to expressly state that data expectations for interchangeability may differ for more complex or less well-understood products.” The group noted that while the BPCIA applies to all biologics, the draft guidance specifies that it “focuses on therapeutic protein products.” Other more complex biosimilars with different mechanisms of action, however, may necessitate switching studies, it said.

In addition, PhRMA contended that the draft guidance “inadequately explains the basis” for the FDA’s change in approach and asked for a more thorough explanation. The group also said it was “concerned about the abruptness of the change in FDA’s approach to interchangeability requirements and FDA’s lack of sufficient public explanation to manufacturers, healthcare providers, pharmacists, and patients” about that shift.

Janssen Research & Development, LLC, a Johnson & Johnson (J&J) company, said the guidance was “an important step in clarifying FDA’s evolving approach regarding biosimilars and the need for switching studies to support interchangeability determinations for a therapeutic protein biosimilar.”

Janssen developed Remicade (infliximab), a reference drug for four FDA-approved biosimilars, none of which have interchangeability status.

A PhRMA member, J&J said it supported that organization’s comments and that it is “imperative” that the FDA provide guidance on five additional points, including “when switching studies are not required” and “the limited cases when clinical data is not needed to establish interchangeability.”

Respondents Urge Stringent Standards

Other groups did not specifically say they disagreed with the draft guidance but expressed concerns about what the implications of it might mean.

For example, while the Coalition of State Rheumatology Organizations (CSRO) said it “appreciates” the “FDA’s evolving confidence in the safety and efficacy of biosimilars,” it expressed concerns about the long-term implications of the guidance. The interchangeable designation should have unique standards, CSRO maintained, and if all biosimilars were deemed interchangeable without additional evaluation, “that would exacerbate existing challenges posed by payer practices in the form of non-medical switching, step-therapy, prior authorization, and other utilization management tactics. Unique standards for granting interchangeability status, though sometimes ignored by payers, provide a necessary safeguard that helps guide clinical decision-making and protects patients from the potentially harmful effects of inappropriate drug switching.”

The National Infusion Center Association (NICA) expressed similar concerns. It also encouraged the FDA to reconsider the guidance, which “only serves to further ‘medical decision making’ by health plans and erode the physician-patient relationship.”

In addition, said CSRO, when patients are moved to a new therapy without their physician being aware, the risk of the nocebo effect — “a phenomenon where patients experience negative side effects simply because they believe the medication has been changed and [no one] told them about it” — is greater, decreasing the product’s efficacy.

The Oncology Nursing Society (ONS) acknowledged biosimilars’ potential to provide more cost-effective treatment alternatives, particularly for people with cancer suffering from “financial toxicity,” but it also cautioned about the nocebo effect.

In addition, it noted that several studies that have found that switching does not affect safety or efficacy primarily involved nononcologic indications such as inflammatory bowel disease or rheumatoid arthritis. ONS urged the FDA to “separately consider the body of evidence for oncologic uses in the guidelines due to the lack of data on multiple switches and no long-term data outcomes for patients with a malignancy which could result in the substantial implications of long-term outcomes, like survival rates, for patients with cancer compared with a non-oncologic diagnosis. This would include the need for close monitoring of discontinuation rates following a switch to a biosimilar, which some studies have shown to increase overtime and could have detrimental health effects to a patient with cancer.”

The Infusion Access Foundation wrote that it is “concerned that the elimination of rigorous study requirements is an oversight that will lead to adverse patient outcomes, delays in care, and increased costs stemming from more expensive alternative treatments.”

Some respondents urged the FDA to not finalize the guidance due to physicians’ lack of confidence in prescribing biosimilars without interchangeability status in place of their reference drugs.

The Alliance for Safe Biologic Medicines, a coalition of physicians, pharmacists, patients and manufacturers of both biologics and biosimilars, said that the guidance was an “ill-advised and inappropriate move,” and that eliminating switching studies “would not only potentially risk patient treatment stability but undermine trust in biosimilars (including interchangeable biosimilars) among patients, physicians and other stakeholders which could ultimately hinder biosimilar acceptance and associated savings to our health system.”

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