Best Pathway To Interchangeable Insulins Is In The Eye Of The Beholder
Executive Summary
Approaches suggested at a US FDA public hearing include allowing follow-on insulins to take a direct route to interchangeability without first having to be approved as biosimilars, and automatically declaring biosimilar insulins interchangeable with one or more reference products.
The US Food and Drug Administration heard a lot of agreement about the need for interchangeable insulins at a 13 May hearing, but different views on how to get there.
Representatives from the biopharma industry and other players in the health care sector, as well as academics and clinicians, suggested various approaches to streamlining the development pathway for interchangeable insulins.
Numerous comments said the agency should be less focused on immunogenicity concerns for insulins than for larger, more complex biologics.
These suggestions included allowing follow-on insulin products to take a direct pathway to interchangeability without first having to be approved as biosimilars, and automatically declaring biosimilar insulins to be interchangeable with one or more reference products.
In addition, numerous commenters suggested the agency should be less focused on immunogenicity concerns for insulins than for larger, more complex biologics.
The FDA convened the public hearing to gather input on scientific standards for evaluating the biosimilarity and interchangeability of insulin products. In March 2020, insulins will transition from regulation as drugs to biologics, which will open the door to submission of 351(k) applications for proposed biosimilar and interchangeable versions of marketed insulins.
Agency officials have framed this regulatory transition, which was required under the Biologics Price Competition and Innovation Act, as integral to injecting more price competition in the insulin marketplace. (Also see "US FDA's Gottlieb Shuts The Door On Exclusivity For 'Transition' Biologics" - Pink Sheet, 11 Dec, 2018.)
Direct Pathway To Interchangeability
Just days before the insulin hearing, the FDA issued long-awaited final guidance on interchangeability. The guidance reiterates the view from the January 2017 draft document that for products intended to be used more than once in a given patient, a switching study generally would be needed to demonstrate the risk in terms of safety or diminished efficacy in switching back and forth is not greater than the risk of using only the reference product.
However, the final guidance allows sponsors to provide justification for why switching study data may not be needed, even for products used more than once. (Also see "Biosimilar Interchangeability Switching Studies May Use Foreign Comparators, US FDA Says" - Pink Sheet, 12 May, 2019.)
Like the draft version, the final guidance describes two pathways by which an interchangeable biosimilar may be licensed, depending upon the product’s complexity. One approach combines the assessment of biosimilarity and interchangeability, while the second pathway calls for postmarketing data for a licensed biosimilar to support an interchangeability designation. (See box.)
Two Paths To Interchangeability
FDA Final Guidance, “Considerations In Demonstrating Interchangeability With A Reference Product”
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“Product A and its associated reference product have relatively low structural complexity and the reference product has no history of inducing severe immune responses related to immunogenicity. Product A also has a low incidence of serious adverse events related to immunogenicity, similar in nature and frequency to those observed with the reference product, as demonstrated in clinical studies conducted as part of the development program for Product A. Here, sufficiently extensive comparative analytical data supporting a demonstration that the proposed interchangeable product (Product A) is highly similar to the reference product, in addition to data derived from an appropriately designed dedicated switching or integrated study (see section VI.A), may be sufficient to support a demonstration of interchangeability.
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“Product B and its associated reference product have high structural complexity and the reference product has a history of rare, life-threatening adverse events related to immunogenicity. Here, postmarketing data for the product as a licensed biosimilar, in addition to an appropriately designed switching study (see section VI.A), may provide additional data and information necessary to support a demonstration of interchangeability. The collection of biosimilar postmarketing data is described further in section V.B of this guidance."
Steven Lucio, VP of the Center for Pharmacy Practice Excellence at the health care performance improvement company Vizient, requested that FDA specifically characterize insulins, which have relatively low structural complexity, as products that can pursue the direct path to interchangeability without first being licensed as noninterchangeble biosimilars.
“Enabling direct pursuit of interchangeability should limit the expense and time invested needed to introduce competition,” Lucio said.
The health care system has a lot of uncertainty about what an interchangeability designation means, and there is a perception that noninterchangeable biosimilars are not as good as interchangeable products, Lucio said. If an insulin product must first be approved as a noninterchangeable biosimilar, uptake could be limited, making it difficult to accumulate the postmarketing surveillance data needed to substantiate interchangeability, he said.
Similarly, Abhijit Barve, Mylan’s head of global clinical research, said interchangeable biosimilars should be able to come to market on the strength of a single, integrated study designed to address biosmilarity criteria in the first part and interchangeability criteria in the second part.
The FDA’s interchangeability guidance discusses an integrated study design in which the first part is intended to demonstrate no clinically meaningful differences with the reference product, and the second part is intended to evaluate the impact of switching for purposes interchangeability.
Speaking on behalf of the American Diabetes Association, Robert Ratner, professor of medicine at Georgetown University, agreed with others who said that biosimilarity absent interchangeability for insulins will not add much benefit but will create confusion.
“I would say go directly to interchangeability and have the requirements there be what’s really required,” Ratner said.
With Biosimilarity Comes Interchangeability
Other speakers advocated for a different type of streamlined approach, taking the view that biosimilarity should equate to interchangeability when it comes to insulins.
Mariana Socal, assistant scientist in the Department of Health Policy and Management at Johns Hopkins Bloomberg School of Public Health, said there is no justification or credible evidence to support requiring additional studies for interchangeability determinations for biosimilar insulins.
“While the criteria established by the BPCIA may be important in order to monitor and safeguard the public in relation to new complex molecules of larger sizes, we contend that this criteria should not be blindly applied to older and smaller molecules like insulin that happen to be produced through biological pathways. Insulin is not Humira.” – Mariana Socal
“FDA has enough authority to issue guidance on its own modifying the criteria for insulin’s interchangeability,” Socal said. “While the criteria established by the BPCIA may be important in order to monitor and safeguard the public in relation to new complex molecules of larger sizes, we contend that this criteria should not be blindly applied to older and smaller molecules like insulin that happen to be produced through biological pathways. Insulin is not Humira.”
“Once we establish the biosimilarity, our position is that there is no differential need for evidence between biosimilarity and interchangeability,” said Sundar Ramanan, VP of global regulatory affairs at biosimilar developer Biocon Ltd.
Unlike with more complex monoclonal antibodies, loss of efficacy due to antidrug antibody formation is not a concern for diabetic patients taking insulin, Ramanan said. Furthermore, while the interval between dosing of mabs may be a week, a month or longer, insulin is taken daily and a multiple-switch study is not needed, he said.
Diabetic patients currently are switched between multiple insulins for a variety of reasons, Ramanan said. “We are asking the agency to consider that when a biosimilar is approved, it should be deemed as interchangeable to all the reference products.”
However, ADA’s Ratner pushed backed on this approach.
“I think that interchangeability needs to be product by product. So the comment that was made earlier about once you have a biosimilar to one, let’s generalize it, I would vigorously disagree with,” Ratner said. “I think it needs to be one for one with interchangeability” to ensure that pharmacokinetics, pharmacodynamics and variability between an interchangeable and its reference product are the same.
“Then hopefully what will happen is rather than switching from [insulin] detemir to glargine, or glargine to degludec, the switch will be made from one form of glargine to another form of the glargine, or one form of degludec to a different form of the degludec,” Ratner said.
Ratner also agreed with other speakers who asserted that immunogenicity is not a major clinical concern with insulin. “I think looking at reproducibility is much more important than looking at immunogenicity.”
Lilly Advocates For More Deliberate Approach
Insulin marketer Eli Lilly & Co. advocated for a less abbreviated, more deliberate approach to determing interchangeability than some of the other commenters.
Sherry Martin, VP of diabetes global medical affairs, said a robust showing of biosimilarity is the first step in demonstrating interchangeability, and the FDA should develop the requirements for insulin products based on a case-by-case assessment of the strength of the biosimilarity data.
“In the case of insulins, the ability to characterize the molecule as a part of the biosimilarity data package may reduce uncertainty at the time of assessment of interchangeability,” Martin said. “This should include a particular focus on those portions of the molecule known to affect immunogenicity. The demonstration of fingerprint-like similarity and functional binding as compared to the reference product may further reduce uncertainty.”
Notably, the FDA removed all references to “fingerprint-like” characterization in the final interchangeability guidance. Industry commenters had complained that the phrase, which appeared in the draft guidance, was not well defined. (Also see "Biosimilars: Postmarketing Data Alone Not Enough For Interchangeability" - Pink Sheet, 17 Jan, 2017.)
Lilly also said that insulin interchangeability determinations for existing product presentations should be separate from evaluations of whether insulins can be used interchangeably as part of a digitally connected treatment system. (Also see "Interchangeable Insulins Could Be Left Out Of Diabetes Treatment ‘Ecosystem’" - Pink Sheet, 13 May, 2019.)