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Demonstrating interchangeability can ensure biosimilar substitutability at the pharmacy level.
In May 2019, FDA published a final guidance (1) on demonstrating biosimilar interchangeability and recommended what analytical assessments and data should be included for a biosimilar to qualify as a substitution for a prescribed originator biologic. Unlike the generic versions of small-molecule innovator drugs, biosimilars cannot simply be substituted for branded biologics.
A generic version of a small-molecule drug has to be shown as being chemically identical to its predecessor, but the term “identical” cannot be used in discussion about biologics for the simple reason that there is variability among lots in all biologics, including reference products, notes SangJoon Lee, senior executive vice-president at Celltrion. “These inherent variabilities are based on factors such as heterogeneous protein production from a living organism cell line and changes in manufacturing processes. The extent of variations in different lots of the original biologic should be measured by biosimilar companies to regard these variations as acceptable boundaries for a biosimilar,” says Lee.
Because biosimilars, unlike smallmolecule drugs, are manufactured in living cell lines using processes that cannot be exactly replicated from one manufacturer to the next, biosimilar manufacturers must demonstrate that the biosimilar is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product in terms of safety and effectiveness, adds Leah Christl, executive director, Global Regulatory and R&D Policy, Amgen.
“An additional showing is needed to support an interchangeability determination,” Christl continues, “If FDA determines that a biosimilar meets the interchangeability standard, that biosimilar may be substituted at the pharmacy under state pharmacy laws.”
“What makes the US biosimilar market different from other highly regulated markets, such as Europe, Canada, Japan, or Australia, is that the regulatory pathway in the United States includes a determination of ‘interchangeability’ between the reference product and biosimilar-a designation that permits pharmacists to substitute a biosimilar for its reference medicine without needing to first obtain permission from the prescribing physician. Without this designation, pharmacists first need to contact and obtain permission from the prescribing physician before they substitute a biosimilar for an originator biologic,” says Hillel P. Cohen, PhD, executive director, Scientific Affairs, Sandoz, a Novartis company.
An FDA-approved biosimilar does not necessarily need an interchangeability designation to be approved for all indications of the originator biologic, however, notes Noelle Sunstrom, founder and CEO of NeuClone, an Australian-based clinical-stage biopharmaceutical company. “For example, while none of the five Herceptin (trastuzumab) biosimilars approved by FDA are designated as ‘interchangeable’, they all are approved for the same indications as the originator. Interchangeability only relates to the practice of a pharmacist substituting a biosimilar for an originator biologic,” Sunstrom emphasizes.
“A major reason a biosimilar is not ‘simply’ designated to be substituted, in the same way as a small-molecule generic, relates to the variable structure of biologic medicines, which can affect their potency and blood half-life in patients,” Sunstrom says. “For small molecules drugs, the precise atomic structure of the originator product is well defined and expected not to change. Thus, following patent expiry of the originator small-molecule drug, another manufacturer can manufacture a generic alternative that is an exact replica of the originator, and can be highly controlled down to the atomic level.”
“However, with biologics, such precise replication cannot be achieved because all biologics-whether an originator or a biosimilar-vary from one batch to the next. This inherent variation is the result of using living cells used to manufacture biologics that are heterogeneous mixtures of different molecules with different post-translational modifications (PTMs). So, biosimilars can be ‘highly similar’ to an originator biologic that itself exhibits batch-to-batch variability,” Sunstrom clarifies.
Variations in PTMs of a protein, including the molecule’s glycosylation profile and formation of di-sulphides, are cell line dependent, says Matt McGann, field applications and marketing manager at RedShiftBio, a Burlington, MA-based provider of analytical instrumentation.
“Many innovator pharmaceutical companies have gone to great lengths to develop unique cell lines for production of a biotherapeutic product, thereby limiting the ability to simply copy a drug substance,” McGann says.
“The processes involved in developing a biosimilar result in variations in the protein from primary to quaternary structure,” McGann continues. “The new FDA guidelines for interchangeability of a biosimilar highlight these differences by recommending that biosimilarity not only be established based in pharmacological attributes of the drug substance but also clinical data, such as clinical end-points and interchangeability. Demonstration of an equal or better patient outcome is considered required evidence to justify the licensing of a biosimilar drug, which is described at the totality of evidence by FDA.”
For practical purposes, clarifying what “interchangeability” means is helpful in biosimilar development. “Interchangeable” means “biosimilar plus,” where the product must first meet the requisite hurdles to qualify as a biosimilar, notes Jennifer Mallory, partner at Nelson Mullins Riley & Scarborough, a Columbia, SC-based law firm. Following this, the biosimilar manufacturer must meet heightened evaluation and testing requirements.
“These are designed to ensure that the biosimilar produces the same clinical result as the approved biologic in any patient and that the safety and efficacy risks arising from switching between the approved biologic and the biosimilar are not greater than the risk of using just the approved biologic,” Mallory says.
The additional hurdles are designed to ensure that a biosimilar may be substituted for the reference biologic without the need for intervention by the health care provider who prescribed the original reference biologic, Mallory adds.
As part of FDA’s standard, a manufacturer of a proposed interchangeable biosimilar product must show the product is highly similar to, and has no clinically meaningful differences from, its reference product, states Christl. Christl also points out that biosimilarity is not equivalent to interchangeability. The latter is intended to support automatic pharmacy-level substitution and needs to be positively established on a case-by-case basis, Christl also says.
“It is important to note that a biosimilar without an interchangeability designation is not inferior to a biosimilar with the designation,” Christl points out. “Instead, an interchangeability designation reflects a determination by FDA that the biosimilar can be substituted for the reference product at the pharmacy without the consent of the prescriber. This determination is based, in part, on additional data showing that patients can be switched back and forth between the reference product and the biosimilar with no additional risk.”
Based on its own internal analyses, Amgen believes that only about 10% of biological products (excluding insulin and human growth hormone) are expected to lose regulatory exclusivity by 2023 in the US. These products are dispensed at retail pharmacies where automatic substitution could occur, Christl notes. “We are seeing many biosimilars contribute to competition and attain strong uptake in the US, even though FDA has not yet designated any biosimilar as interchangeable.”
Christl also states that FDA’s interchangeability guidance does not substantively address analytical testing or analytical standards beyond what the agency already has addressed in earlier guidance on the demonstration of biosimilarity. “In terms of clinical testing, FDA’s interchangeability guidance states that sponsors seeking an interchangeability designation for a product intended to be used more than once by an individual are generally expected to conduct switching studies, in which patients start with the originator product and are randomly assigned to switch to the biosimilar or continue using the originator product. According to the guidance, the ‘switching’ group would be expected to incorporate at least two switches between the originator and biosimilar products and at least two exposures to each product,” says Christl.
“Amgen believes that FDA’s current standards for demonstrating interchangeability are scientifically appropriate,” she adds.
“It is quite important for a biosimilar to demonstrate ‘interchangeability’ because, unlike generics, a biosimilar can be prescribed by physicians under the current law. Despite biosimilar use over the years, there has been a hesitation to prescribe them because of potential risks, such as diminished efficacy or expectation of immunogenicity after switching to a biosimilar,” says Lee. Lee notes, however, that the designation of interchangeability based on efficacy results from multiple switching will encourage physicians and patients to use biosimilars more often. Furthermore, interchangeability status ultimately allows for any product among available interchangeable products to be dispensed at pharmacy level, which is expected to accelerate access to biosimilars.
The interchangeable designation in the US requires additional clinical data beyond that provided to establish biosimilarity, Cohen points out. “It is not a higher quality standard because an interchangeable biologic and biosimilar, by definition, match the reference product in safety, purity, potency, and efficacy.
The importance of interchangeability is particularly relevant for biologics dispensed by pharmacists for patients with chronic illnesses because these patients require treatment over a long period of time, notes Sunstrom.
However, Sunstrom explains, if a treatment is only for a short duration, such as with many oncology biologics, the patient can receive fewer doses, thereby reducing the opportunity for switching between an originator and biosimilar. If the prescriber is also administering the biologic (i.e., no decision by the pharmacist), the prescriber has total control over whether an originator or biosimilar is administered with no opportunity for pharmacy-level substitution, making an interchangeability status in cases such as these less significant.
“Note that, as of March 12, 2020, none of the 26 FDA-approved biosimilars have been designated as interchangeable,” Sunstrom observes.
Further, there has been debate over the need for an FDA interchangeability designation at all. “Interchangeability is an additional attribute to a biosimilar that comes at a substantial investment in clinical trial design, which incorporates switching originator with biosimilar and back again in large-patient-number trials. It does not designate the interchangeable biosimilar as being superior in any way to those without this designation,” Sunstrom states.
Cohen holds a similar opinion, saying that, as a scientific matter, a biosimilar is developed to match its reference medicine with regard to these attributes. “Therefore, it is our position that an approved biosimilar should be considered interchangeable with its reference medicine, meaning that a patient can expect an equivalent treatment outcome,” Cohen adds.
“To date, there are 26 FDA-approved biosimilars, but only 16 are marketed in the US [as of press time]. In comparison, the European Medicines Agency (EMA) has approved 64 biosimilars, 59 of which are available for use in Europe. While we are encouraged that healthcare systems in the US are implementing biosimilars into their clinical practices at a growing rate, there are still hurdles that need to be addressed to support a biosimilar market that can generate success like what we’ve seen in Europe,” states Cohen.
One hurdle includes the challenges posed by FDA’s approval process for interchangeability, specifically, the fact that to obtain interchangeability, sponsors are required to conduct an extensive, comparative pharmacokinetic (PK) study using multiple switches followed by an extended follow-up period. “This criterion is not mandated for PK studies of originator biological drugs when manufacturing process changes are implemented that lead to structural changes of the biological drug itself. The additional research burden and costs for a biosimilar drug to be considered interchangeable are substantial and may deter biosimilar manufacturers from seeking interchangeability,” Cohen emphasizes.
The value of the interchangeable attribute, therefore, is in the automatic substitution at the pharmacy level. “In Europe, there is no equivalent designation from the European Medicines Agency (EMA) and switching between originators and biosimilars is a medical matter typically at the discretion of the prescribing physician, not the pharmacist. As argued by Ebbers & Schellekens (2019), biosimilars should be interchangeable by default rather than needing to meet additional requirements to be designated as such: ‘there is no reason to doubt that biosimilars are interchangeable and that the risk of increased immunogenicity of switching to a biosimilar is no greater than switching between two batches of any biologic. We argue that the default should be that biosimilars are interchangeable, unless there is compelling evidence otherwise’.” Sunstrom cites (2).
When it comes to analytical recommendations in the FDA interchangeability guidance, a key phrase to take note of is in Section V.A.1.: “Advances in analytics may allow for extended analytical characterization that affect the extent of other data and information needed to support a demonstration of interchangeability…” (1).
McGann points out that this statement highlights the fact that improvements in analytical methods for characterizing biotherapeutics can drastically impact the totality of evidence required to support the claims of biosimilarity. “Improvements in instrumentation capabilities, such as sensitivity, resolution, or precision that can more clearly demonstrate biological similarity could reduce the burden of proof required to demonstrate both biosimilarity and interchangeability,” McGann says.
Advanced analytical tools (e.g., AQS3pro, RedShiftBio) can offer a 30x improvement in sensitivity and the ability to measure secondary structure in formulation conditions. The latter measurement was not previously possible, and it could provide evidence of biosimilarity that reduces the burden of proof in other areas, McGann says.
“For this reason, biosimilar developers need to ensure that their analytical tools are at the cutting edge of technology. As a company, they need to be constantly reviewing their capabilities to ensure that they stay at the forefront of technology relative to the market,” McGann adds.
“FDA, in recent years, has taken less of a prescriptive stance when it comes to what types of analytical characterization should be used, preferring to move the responsibility to the pharmaceutical company to justify why a measurement is not required rather than requesting specific tests to be performed. This change can be attributed to the rapid change in technology in recent years,” explains McGann.
Celltrion backs up that perspective. Lee says that, instead of providing any specific analytical recommendations that biosimilar developers can implement, the new guidance explains the agency’s position, which discusses the planned development approach. This approach includes any proposed justification for reducing the extent of information needed to support a demonstration of interchangeability by the extended analytical characterization. “Our company is planning to discuss reasonable approaches for each product with the regulatory authority to reduce the burden of clinical trials,” Lee states.
What the guidance does provide are examples that sponsors may employ as benchmarks to assess the approaches they are thinking of using to demonstrate interchangeability and to develop their product development plan, says Mallory. Mallory also notes that it is advisable to identify the approaches highlighted in the guidance document that a sponsor already used in its development work and previously submitted to FDA in connection with the biosimilar approval process. “Likewise, sponsors would be well-served to determine which approaches in the guidance document do not appear applicable (and why), and any short cuts that potentially may be available. Some of this analysis ideally would take place even before early discussions with FDA so that the sponsor can be comfortable with the specific goals and objectives that it would like FDA to green-light or begin to consider,” she highlights.
An important theme in the guidance, Mallory emphasizes, is that FDA is not suggesting that there is a one-size-fits-all approach for demonstrating interchangeability. Rather, the agency used the guidance to confirm that demonstrating interchangeability is complex, much like the complex molecules involved. “Thus, FDA noted in the guidance that the ‘data and information necessary to support a demonstration of interchangeability need to be considered on a case-by-case basis.’,” Mallory says.
Given FDA’s perspective, it is therefore helpful that the guidance repeatedly emphasizes that sponsors are encouraged to reach out to the agency to conduct early discussions and schedule meetings. “Additionally, as stated in the Federal Register notice regarding the guidance, FDA is not suggesting that this will be its final word on interchangeability. Indeed, in February 2020, FDA issued additional draft guidance, entitled Biosimilars and Interchangeable Biosimilars: Licensure for Fewer than All Conditions of Use for Which the Reference Product Has been Licensed(3). We can expect upcoming agency guidance and other actions that hopefully will provide more insight for developers of biosimilars and interchangeable biosimilars,” Mallory concludes.
“The analytical processes and tools used in biosimilar development are very similar to those used in the development of originator biological products. The primary difference is how those tools are used in the iterative process of biosimilar development. While the methods and tools are technically complex (thus, not simple), they can be utilized in a fairly straightforward manner to develop biosimilars that meet the criteria of ‘highly similar with no clinically meaningful differences’,” Christl adds.
1. FDA, Guidance for Industry, Considerations in Demonstrating Interchangeability with a Reference Product Guidance for Industry (CDER, CBER, May 2019).
2. H.C. Ebbers and H. Schellekens, Drug Discovery Today, 24 (10) 1963–1967 (2019).
3. FDA, Draft Guidance for Industry, Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed Guidance for Industry (CDER, CBER, February 2020).
Vol. 33, No. 4
When referring to this article, please cite it as F. Mirasol, “Biosimilars Tackle Interchangeability Standards,” BioPharm International 33 (4) 2020.