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FDA released a long-awaited draft guidance to help sponsors seeking to demonstrate interchangeability for biosimilar products.
A draft guidance covering biosimilarity is finally here-in 2017-even though it was originally on the guidance agenda for 2016. The guidance relies heavily on switching studies between a reference product and a biosimilar and proving that such switches remain safe and clinical results remain unchanged. A product must first be deemed a biosimilar, and an interchangeability determination can follow, according to the documents. The agency supports switching studies because it believes these studies most accurately reflect how an interchangeable product will be used in clinical practice.
To support an interchangeability designation, product sponsors must submit data on the critical quality attributes, analytical differences, mechanisms of action, pharmacokinetics, immunogenicity risk, differences in potential toxicities, and any other safety information that is relevant for both a reference product and a biosimilar product.
Differences between products related to their specific mechanisms of action, such as any differences in glycosylation profiles, will need to be presented to the agency. These product differences should not confer any significant differences in clinical benefit or safety. FDA admits that not all current analytical methodologies may characterize all relevant structural differences between products, so data sets should include information around things such as charge variants and glycoforms to “reduce the residual uncertainty about interchangeability.” Additionally, the agency notes that postmarketing surveillance data from the licensed biosimilar product may be necessary for a sponsor to make its case that there are no clinically meaningful differences between a reference product and a biosimilar.
A sponsor may seek interchangeability licensure for fewer indications than for which the reference product is licensed, which could prove to be challenging when it comes time to label said product with a meaningless suffix.
If patients in switching studies experience an adverse immune response, FDA acknowledges that “carryover effect” may make it difficult to tell if the reference product or the proposed interchangeable was the cause of the adverse event. Although it may be difficult to prove the cause, FDA says the appearance of an adverse event would still “raise concerns” about the interchangeability of a biosimilar. Thus, relevant pharmacodynamics data may help illustrate domains of activity and help a sponsor’s case.
Lead-in periods should be sufficient to ensure a patient has seen the effect of a medication before he or she is switched to the biosimilar, and there should be at least three switching events to the alternate product, with the last switch being from the reference product to the alternate product. The agency also suggests using a non-switching proposed product arm through the duration of the switching studies to serve as a control.
FDA said it expects that switching studies be included in applications for interchangeable products; however, the “originator” products that will serve as controls may not be sourced from outside of the United States. Although biosimilar sponsors can use data from non-US sources to prove biosimilarity, they may NOT use these data to support an interchangeability designation. Because of small structural differences in products, such as acidic variants or deamidations, the overall immune response could be increased as a result of multiple exposures to different products, the agency notes.
Plus, the agency says, establishing interchangeability with a product that would primarily be used outside of the US “would generally not be appropriate,” as it would not be representative of a real-life clinical option for patients. But, FDA did not elucidate how originator manufacturers would provide product to biosimilar applicants or if originator companies would be required to provide enough samples to biosimilar applicants for comparability purposes.
FDA also says that a product should “generally” not be considered for an interchangeability status if the method of drug delivery differs from that of the originator product. Thus, a drug made in a prefilled syringe cannot be considered for auto-injector packaging, unless the changes do not negatively impact patients nor require additional training for proper use. If the packaging design differs for the biosimilar, FDA may require additional studies showing that the design differences won’t impact administration of the medication.
Although interchangeability was not proposed nor requested in Celltrion’s biologics license application (BLA) for Inflectra (called Remsima in Canada and other regions), the company did present some preliminary switching data in its BLA. FDA wrote in a briefing on that data, “the single transition from EU-approved Remicade to CT-P13 during the long-term extension studies in RA and AS did not result in worse safety or immunogenicity profile. This would support the safety of a clinical scenario where non-treatment naïve patients undergo a single transition to CT-P13.” Despite the fact that the agency acknowledged at the time of Inflectra’s review that Celltrion’s switching data could theoretically support an interchangeability status, it would appear that the agency has backtracked on this statement-the EU-approved Remicade could not actually be used in switching studies because of its origin of manufacture. More than 30 distinct orthogonal methods were used to evaluate the analytical similarity of Inflectra to Remicade, so sponsors should expect to present results for numerous types of analytical tests.