This post, Part II, of a three-part series (Part I) on FDA’s interchangeability draft guidance, highlights the key issues that were raised in the stakeholder comments provided to FDA.  FDA received 52 comments in total from a variety of stakeholders, including patients, physicians, insurers, innovators and biosimilar makers.  The stakeholders were divided in their views in a number of areas.  Patient and physician groups and innovators urged FDA to adopt more stringent requirements for interchangeability assessments.  Biosimilar makers and insurers, by contrast, generally pressed for a loosening of the guidance provided by FDA as well as clarification that interchangeable biosimilar products were not more similar to the innovator product than the non-interchangeable ones.  The comments also raised a number of issues not addressed by the guidance, which will be discussed in the third post in this series. 

• A Higher or Just Different Standard of Review

Biosimilar makers expressed concern that FDA’s guidance on interchangeability and a designation of interchangeability in general implies that interchangeable biosimilars are subject to a higher standard of review and therefore may be perceived as safer and more effective than their non-interchangeable counterparts.  Innovators, such as AbbVie, stressed that the standard for interchangeable biosimilars is necessarily higher, not just different, as reflected in the US biosimilars statute (BPCIA), because interchangeable biosimilars can be substituted at the pharmacy level without intervention of physicians.

Sandoz, a leading biosimilar maker, for example, called on FDA to clarify that “interchangeability is a requirement for additional data not a higher standard” and that an interchangeability designation merely represents “additional information available for pharmacists.”  It urged FDA to state that “an interchangeability designation requires additional data but does not represent a higher standard for product quality or safety and efficacy beyond that required to meet a biosimilarity designation.”  Similarly, Pfizer, an innovator and biosimilar maker, emphasized that “[a] designation of interchangeability should not be perceived to relate to the quality, safety, or effectiveness of the product.” 

AbbVie, a leading innovator company, stressed that Congress “established interchangeability as a different and higher standard than biosimilarity.” AbbVie explained that “Congress sought to ensure heightened protection for ‘any given patient’ who could face a change in therapy without the intervention of his or her physician.”  The BPCIA also rewards the first interchangeable biosimilar product with exclusivity against other interchangeable biosimilars that non-interchangeable biosimilars do not enjoy.  Patients for Biologics Safety & Access (PBSA) similarly stressed that the standard for approval is higher, not just different.  It said that the final guidance on interchangeability should reflect “the clearly different and higher standard for interchangeability provided by Congress to protect patient safety.”  It discussed that Congress required interchangeable biosimilars to be “both biosimilar to an FDA-approved reference product, and … be expected to produce the same clinical result as the reference product in any given patient.”  PBSA noted that Congress placed an even “higher standard” for interchangeability for products that are given more than once: “the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be greater than the risk of using the reference product without alternating or switching.”

• Clarity on “Fingerprint-like Characterization”

Stakeholders uniformly urged FDA to define terms such as “fingerprint-like characterization” or “fingerprint-like similarity” and explain how they relate to interchangeability and how they may be achieved.  Pfizer noted that FDA’s statements in the guidance relating to “fingerprint-like characterization” may undermine confidence in non-interchangeable biosimilar products and promote “inaccurate perceptions of the quality, safety, or effectiveness of biological products based on their licensure pathway.”  Sandoz stated that a biosimilar that is not designated as “fingerprint-like” may be perceived as “less similar or good.”   It urged FDA to clarify that “fingerprint-like similarity” has no such implications. 

The Biotechnology Innovation Organization (BIO) asked FDA to provide examples of specific tools and processes that could be used to demonstrate “fingerprint-like similarity” and to explain how FDA intends to use the concept to reduce the scope and extent of clinical studies.  BIO also urged FDA to clarity that “fingerprint-like similarity” to the reference product does not imply superiority in terms of the quality, safety and efficacy and does not mitigate the need for post-market surveillance.  Amgen, an innovator and biosimilar maker, noted that there is no real-world example of a biosimilar that has been shown “fingerprint-like similarity” with the reference product to date and asked FDA what is required to obtain such a classification.   

• Using US-licensed Reference Products Only in Switching Studies

Innovators, patients and physicians endorsed FDA’s strong preference for using a US-licensed reference product in switching studies to demonstrate interchangeability.  Biosimilar makers, pharmacy groups and insurers, by contrast, opposed it for a variety of reasons, including expense and impracticality. 

Alliance for Patient Access (AfPA), for example, stated that “since patients will be prescribed US-licensed products, it follows that clinical trials should utilize US-licensed reference products in [] switching studies.” AfPA member physicians indicated that the use of US-licensed reference products would “increase their confidence” in the switching studies.  Coalition of State Rheumatology Organizations (CSRO) also agreed that US-licensed reference product had to be used in the switching studies given the potential for differences between US and international products.  CSRO explained that while the differences may be subtle, they had the potential to render studies based on non-US reference product “useless” to prove interchangeability for US patients.  Other physician and patient groups, BIO, PhRMA and innovators expressed similar views.

CVS Health, Cigna and the Ohio Public Employees Retirement System (OPERS), by contrast, pointed out that biosimilar makers seeking interchangeability status may encounter difficulty accessing US-licensed reference products and that US-licensed reference products may be more expensive than elsewhere.  Pfizer added that the need for US-licensed reference product “may dictate the conduct of switch studies within the U.S.” where it may be impractical to recruit a sufficient number of patients for a switch study since access to biologics in the US is greater than in most of the world.   Sandoz expressed similar concerns and asked FDA to “provide greater openness and flexibility to accept use of non-US licensed reference product to seek approval of an interchangeable biologic if scientifically justified.” 

• Endpoints Aside From PK/PD in Switching Studies

A number of stakeholders criticized the draft guidance’s use of PK/PD as the primary endpoints in switching studies.  For example, Johnson & Johnson explained that PK and PD may not detect significant immunogenicity differences.  J&J therefore urged FDA to include direct measures of immunogenicity among the primary endpoints.  BIO and AbbVie, among others, also urged a comprehensive immunogenicity assessment. 

• Giving Effect to the “Any Given Patient” Requirement

Innovators as well as physician and patient advocacy groups commented that FDA’s draft guidance gave short shrift to the “any given patient” requirement for interchangeable products.   For example, AbbVie explained that the population-level assessments described in FDA’s guidance did not satisfy the requirement that the interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient” since such assessments “can mask for small subsets of patients who may not tolerate a switch between a reference product and a biosimilar.”  PBSA also urged FDA to look “beyond averages for populations” and to analyze “subsets of various populations.”  PhRMA asked FDA to recommend “statistical approaches that assess subject-by-formulation interaction variance as part of the switching study to demonstrate that that the ‘any given patient’ requirement has been met.”  BIO expressed similar views.

• Interchangeability All Conditions of Use

Many stakeholders agreed with FDA that biosimilar makers should demonstrate interchangeability for each and every condition of use for which the reference product is licensed even if licensure is not sought for all the conditions of use.  Pfizer explained that this is important since if “a biosimilar sponsor were unable to scientifically support extrapolation of clinical data across each condition of use, one could argue that the statutory requirement that the biological product ‘can be expected to produce the same clinical result as the reference product in any given patient’ has not been met.”  Similarly, the Biosimilars Forum stated that “regardless of whether licensure is sought for all indications, to meet the statutory definition of interchangeable, the sponsor must scientifically justify licensure for all indications – whether through testing or extrapolation.”  PhRMA urged FDA to clarify that demonstrating interchangeability for each of the reference product’s approved conditions of use is a statutory requirement.  By contrast, the Association for Accessible Medicine (formerly the Generic Pharmaceutical Association) and the Biosimilars Council, argued that FDA did not have authority to require data and information on indications of use for which the biosimilar maker was not seeking approval. 

• Product Presentations and Interchangeability

The Biosimilars Forum expressed concern that FDA’s view that the presentation for interchangeable products should generally be the same as that for the reference product “could limit innovation, such as the use of novel delivery methods that may reduce user error or otherwise improve patient usage.”  Innovators, by contrast, voiced concern about patients trained to use the reference product receiving an unfamiliar device at the pharmacy level without the intervention of the health provider.  PhRMA urged FDA to consider “whether patients with significant experience with the reference product presentation may be at an increased risk of confusion and use-related errors upon substitution of a presentation with design differences without training or other intervention.” 

• Product Drift and New Conditions of Use

FDA asked for comments on how to address post-approval manufacturing changes of interchangeable products as well as new conditions of use for the reference product after approval of the interchangeable product.  The comments were varied. Boehringer Ingelheim, a biosimilar maker and innovator, “implore[d]” FDA to regulate post-approval manufacturing changes as it does for any biologic and saw no need to revisit interchangeability determinations due to new conditions of use.  Sandoz also stated that it “emphatically believe[d] that no new regulatory processes need to be established beyond those already in place for review and approval of manufacturing changes for all biologics.”  By contrast, Genentech, and others, stressed that interchangeability “is a point in time assessment” and that a biosimilar product may cease to be interchangeable with the reference product over time due to product drift.  As to new conditions of use, PhRMA asked FDA to require biosimilar makers to provide scientific justification for interchangeability as to any new indication in order to maintain a product’s designation as an interchangeable product.  PhRMA expected biosimilar makers “rarely would encounter scientific difficulties in providing such justification.”