First Interchangeable FDA Approval Without Study of Change | Venable LLP


[co-author: April Breyer Menon]

Cimerli™ (ranibizumab-eqrn) was approved by the FDA on August 2, 2022 as interchangeable with Lucentis® (ranibizumab). Cimerli is the third interchangeable biosimilar approved in the United States, after Semglee® (insulin glargine-yfgn)interchangeable with lantus® (insulin glargine)in July 2021, and Cyltezo® (adalimumab-adbm)interchangeable with Humira® (adalimumab)in October 2021. As interchangeable, Cimerli may be automatically substituted at the pharmacy, subject to state law, such as generic small molecule drugs. Because Cimerli was the first interchangeable to be approved for Lucentisit will receive 12 months of exclusivity where no other Lucentis interchangeable can be approved. When it is launched in October 2022, it will still have to face competition from Lucentis biosimilar Byooviz™ (ranibizumab-nuna)approved in September 2021 and launched in June 2022.

Cimerli was approved for the five by Lucentis indications including neovascular (wet) age-related macular degeneration (AMD), macular edema after retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), and neovascularization choroidal myopia (mCNV), based on the Phase III COLUMBUS-AMD head-to-head versus Lucentis. Unlike all other interchangeables approved to date, Cimerli was approved without a switch study.

For a biosimilar to be approved as an interchangeable, the FDA requires additional information to show that the biosimilar “can produce the same clinical outcome as the reference product in a given patient” 42 USC § 262(k)(4)(A )(ii) and “for a biological product administered more than once to an individual, the risk in terms of safety or reduced efficacy of alternating or switching between the use of the biological product and the product of Reference is not greater than the risk of using the Reference Product without such alternation or change. 42 USC § 262(k)(4)(B). Generally, the FDA expects a switch study to be necessary to demonstrate the safety and risk assessment of the switch. Although, in its draft guidance “Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products,” the FDA has suggested that a switchover study may not be necessary in certain circumstances, particularly with respect to insulins.[1]

Cimerli is the first example of an interchangeable agreement that does not require a commutation study. In this situation, the FDA did not believe that a switching study would be informative as to the safety risks or diminished efficacy associated with switching between Cimerli and Lucentisnoting that the request for Cimerli included “a comprehensive and robust analytical assessment that compared the structural and functional characteristics of Cimerli (ranibizumab-eqrn) at Lucentis (ranibizumab injection) and other clinical data on safety, immunogenicity, and efficacy, to support the FDA’s decision that a switch study was not required to support approval of Cimerli as interchangeable with Lucentis.”[2]

It’s unclear whether this means switching studies will be less likely in the future, as the FDA determines interchangeability on a case-by-case basis. It was suggested that one possible reason why studies of change were not necessary for Cimerli it is because the eye is a privileged immune environment,[3] meaning that foreign antigens generally do not trigger immune responses here. It is possible that drugs targeting other immune privileged sites such as the central nervous system and the brain may also not require a change of studies under this rationale, but that remains to be seen.

The impact of fewer studies needed to demonstrate interchangeability is substantial, as studies of change are expensive and time-consuming. Patients could benefit more quickly from reduced prescription costs if interchangeable products were brought to market more quickly due to less need for extensive testing. Although the full benefits of an interchangeability designation remain unclear, given that the prescribing and payment dynamics of biologics are complicated, it is likely that developers of biosimilars will use Cimerli’s approval process as a roadmap for future interchangeable development programs.

[1] Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products, November 2019 Draft Guidance for Industry, available at

[2] Z. Brennan, “Interchangeability without changing studies: the FDA explains why a new Lucentis biosimilar can be a game changer”, Endpoints News, available at game/.

[3] Identifier.


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