Biosimilar interchangeability: What it means for clinicians

By Edward C. Li, PharmD, MPH, BCOP

The FDA in January released its draft guidance for a biosimilar to achieve the interchangeability designation.

A comment period is set to end May 9, with final guidance to follow.

Edward C. Li

Although this document is clearly geared toward biosimilar manufacturers to help them develop an application to achieve the interchangeability designation, this long-awaited guidance has important implications for clinicians because of how the interchangeability designation for biosimilars will affect practice.

According to the Biologics Price Competition and Innovation Act of 2009 — the provision that kicked off the FDA working group to create an abbreviated approval pathway for biosimilars — an interchangeable biosimilar is one that “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Therefore, these products essentially would behave similarly to generic products within clinical practice, wherein the pharmacist will use professional autonomy and judgment to dispense a clinically equivalent and lower-cost product.

Meaning of interchangeable

Biosimilars undergo extensive development to ensure the products are demonstrably highly similar to their reference drug in terms of physiochemical, functional and biopharmaceutical characteristics, as well as clinical efficacy and safety.

Human clinical studies rigorously compare the biosimilar with the reference in terms of human pharmacokinetics, pharmacodynamics, efficacy and safety, including immunogenicity.

Although the FDA does not require clinical testing in all indications — unlike for novel molecules — the biosimilar can be approved for all of the reference product’s indications if it can be scientifically justified through a robust understanding of the biologic’s mechanism of action, potential differences in population pharmacokinetics, immunogenicity/safety risk and the overall data package of the biosimilar.

The process of making a biosimilar product — from conception to approval — can take 8 to 10 years.

In order to be recognized by the FDA as interchangeable with its reference product, the biosimilar biological product must meet additional regulatory standards beyond being “biosimilar” to the reference product.

These standards must demonstrate that the biosimilar is “expected to produce the same clinical result as the reference product in any given patient,” and that there is no loss of efficacy or safety when switching between the biosimilar and reference product.

The draft FDA guidance for demonstrating interchangeability would require a “dedicated switching study” design, in which patients start with the reference product and are randomly assigned to switch to the biosimilar or continue using the reference product. The “switching” group would be expected to incorporate at least three switches between the reference and biosimilar products.

The FDA states that the primary endpoints of switching studies must be pharmacokinetic and pharmacodynamic in nature to determine if there are any concerns with immunogenicity. Assessment of additional safety and immunogenicity parameters must be incorporated into the study design.

In cases in which there are rare but serious safety risks with the reference product — and, subsequently, the biosimilar — postmarket monitoring may play a role in informing interchangeability. This is because these safety risks largely would go underreported in premarket clinical trials because the sample sizes within these studies are not large enough to assess rare events.

Pharmacovigilance with active and passive surveillance programs help to inform the interchangeability exercise.

Clinician expectations

As with the data required to demonstrate biosimilarity, the data required by the FDA to obtain a designation of being “interchangeable” are drastically different than the data required to demonstrate safety and efficacy for new novel products.

Accordingly, clinicians should expect the studies that demonstrate interchangeability will not utilize the same endpoints and sample size as one would use to demonstrate clinical utility.

Dedicated switching studies that evaluate pharmacokinetic/pharmacodynamic endpoints — and possibly postmarket studies for some molecules — are the norm. We should not come to expect a large randomized controlled trial of OS or PFS because this study design is not adequately sensitive enough to detect issues with immunogenicity.

For some molecules, postmarket studies will help to inform the interchangeability designation. Therefore, clinicians should be well attuned to their roles within pharmacovigilance programs, whether they are active — eg, studies that utilize claims data to evaluate outcomes — or passive, such as voluntary adverse event reporting to the FDA.

The impact of the potential accumulation of antidrug antibodies are a major concern. One important question is if the loss of efficacy due to antidrug antibodies will be reported as an adverse event or categorized differently.

Regardless, clinicians should be encouraged to voluntarily submit adverse events, and to be mindful of correctly attributing the adverse event to the correct product.

To this end, the FDA has decided to utilize a four-letter suffix after a biological product’s “proper” name to distinguish the biosimilar and help clinicians correctly identify what product was administered. It is important to note that the FDA has not ruled on how to name interchangeable biosimilars.

Commitments to postmarketing pharmacovigilance programs may be mandated as part of the interchangeability determination, and they will be critical to confirming or negating the designation. Pharmacovigilance, of course, requires the input of clinicians, and correct attribution of adverse effects in order to be valuable.

Substitution process

Within the medication use process — prescribing, dispensing and administration — the interchangeability designation plays a major role in that many state pharmacy practice laws allow pharmacists to independently substitute a biosimilar for the reference if it is designated as interchangeable by the FDA.

Twenty-six states have passed biosimilars substitution bills to this effect, with some stipulations similar to generic substitution laws. For example, prescribers would retain the ability to write “dispense as written” if they do not want a biologic substitution made, just as they do for a generic product.

However, there are some differences in the process:

  • Pharmacists are not able to legally substitute biosimilars for the reference product outside of obtaining a new prescription. If the prescription is written based on the reference product’s name, the patient’s out-of-pocket costs may be higher based on the patient’s insurance benefit design. Consequently, prescribers must specify which product should be dispensed to the patient.
  • If interchangeable biosimilars are available and the prescriber has no preference about the specific product given, the prescriber should write the prescription based on the reference product’s name so the pharmacist can decide which product will be dispensed.
  • If a prescriber has a specific product in mind — whether it is a biosimilar or reference product — the actual product’s name should be stated, with a note that substitution is not permissible.

These added steps are a departure from our experience with generic drugs.

Additional stipulations within these substitution laws aim to further facilitate pharmacovigilance and ensure patient safety by requiring the pharmacist to notify the prescriber when substitution occurs.

Formulary decisions for interchangeable biosimilars also will rely heavily on whether a product is deemed to be interchangeable.

It is important to note, however, that biosimilars with additional efficacy studies are not necessarily “better” or “more interchangeable” than other products. In fact, because efficacy studies are not required to determine interchangeability as per FDA regulations, clinicians should not expect these trials to be available for the majority of biosimilars, regardless of whether they receive interchangeability designation.

In contrast, the availability of clinical data of a particular biosimilar may sometimes be indicative of FDA concern.

Biosimilar companies may only conduct these trials if required by the FDA due to concerns about the comparison of quality attributes or pharmacokinetics/pharmacodynamics data between the biosimilar and reference product.

Overall, the biosimilar clinical drug development environment continues to evolve, and it will take time for clinicians and patients to become comfortable using biosimilars.

We can draw on the experience of early adopters and of our colleagues in Europe, and our comfort level may be heightened as biosimilars products seek to achieve the formal designation as being “interchangeable.”

The expectations for biosimilars, and the policies related to the use of these agents, should balance cost considerations with scientific justification and the rigorous need for evidence.

As of press time, the FDA had not designated any biosimilars as interchangeable, and it may be some time before we see any.

Biosimilars themselves have been slow to make it to market. In hematology/oncology, the only FDA–approved biosimilar is filgrastim-sndz (Zarxio, Sandoz), a biosimilar of filgrastim (Neupogen, Amgen). Apobiologix is awaiting an FDA decision on its own biosimilar version for this same product.

The FDA also is reviewing applications submitted by Apobiologix, Coherus BioSciences and Mylan for biosimilars to pegfilgrastim (Neulasta, Amgen).

Hopefully, as the FDA provides more clarity on the pathways for biosimilars, these newer biologics will make it into the hands of clinicians sooner.

Reference:

FDA. Considerations in demonstrating interchangeability with a reference product: Guidance for industry. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/UCM537135.pdf. Accessed on May 5, 2017.

For more information:

Edward C. Li, PharmD, MPH, BCOP, is associate professor in the department of pharmacy practice at University of New England College of Pharmacy in Portland, Maine. He is a board-certified oncology pharmacist who maintains a practice with New England Cancer Specialists and develops cancer treatment pathways with New Century Health. He can be reached at eli@une.edu.

Disclosure: Li reports financial relationships with Apobiologix, Eli Lilly and Pfizer.

By Edward C. Li, PharmD, MPH, BCOP

The FDA in January released its draft guidance for a biosimilar to achieve the interchangeability designation.

A comment period is set to end May 9, with final guidance to follow.

Edward C. Li

Although this document is clearly geared toward biosimilar manufacturers to help them develop an application to achieve the interchangeability designation, this long-awaited guidance has important implications for clinicians because of how the interchangeability designation for biosimilars will affect practice.

According to the Biologics Price Competition and Innovation Act of 2009 — the provision that kicked off the FDA working group to create an abbreviated approval pathway for biosimilars — an interchangeable biosimilar is one that “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Therefore, these products essentially would behave similarly to generic products within clinical practice, wherein the pharmacist will use professional autonomy and judgment to dispense a clinically equivalent and lower-cost product.

Meaning of interchangeable

Biosimilars undergo extensive development to ensure the products are demonstrably highly similar to their reference drug in terms of physiochemical, functional and biopharmaceutical characteristics, as well as clinical efficacy and safety.

Human clinical studies rigorously compare the biosimilar with the reference in terms of human pharmacokinetics, pharmacodynamics, efficacy and safety, including immunogenicity.

Although the FDA does not require clinical testing in all indications — unlike for novel molecules — the biosimilar can be approved for all of the reference product’s indications if it can be scientifically justified through a robust understanding of the biologic’s mechanism of action, potential differences in population pharmacokinetics, immunogenicity/safety risk and the overall data package of the biosimilar.

The process of making a biosimilar product — from conception to approval — can take 8 to 10 years.

In order to be recognized by the FDA as interchangeable with its reference product, the biosimilar biological product must meet additional regulatory standards beyond being “biosimilar” to the reference product.

These standards must demonstrate that the biosimilar is “expected to produce the same clinical result as the reference product in any given patient,” and that there is no loss of efficacy or safety when switching between the biosimilar and reference product.

The draft FDA guidance for demonstrating interchangeability would require a “dedicated switching study” design, in which patients start with the reference product and are randomly assigned to switch to the biosimilar or continue using the reference product. The “switching” group would be expected to incorporate at least three switches between the reference and biosimilar products.

PAGE BREAK

The FDA states that the primary endpoints of switching studies must be pharmacokinetic and pharmacodynamic in nature to determine if there are any concerns with immunogenicity. Assessment of additional safety and immunogenicity parameters must be incorporated into the study design.

In cases in which there are rare but serious safety risks with the reference product — and, subsequently, the biosimilar — postmarket monitoring may play a role in informing interchangeability. This is because these safety risks largely would go underreported in premarket clinical trials because the sample sizes within these studies are not large enough to assess rare events.

Pharmacovigilance with active and passive surveillance programs help to inform the interchangeability exercise.

Clinician expectations

As with the data required to demonstrate biosimilarity, the data required by the FDA to obtain a designation of being “interchangeable” are drastically different than the data required to demonstrate safety and efficacy for new novel products.

Accordingly, clinicians should expect the studies that demonstrate interchangeability will not utilize the same endpoints and sample size as one would use to demonstrate clinical utility.

Dedicated switching studies that evaluate pharmacokinetic/pharmacodynamic endpoints — and possibly postmarket studies for some molecules — are the norm. We should not come to expect a large randomized controlled trial of OS or PFS because this study design is not adequately sensitive enough to detect issues with immunogenicity.

For some molecules, postmarket studies will help to inform the interchangeability designation. Therefore, clinicians should be well attuned to their roles within pharmacovigilance programs, whether they are active — eg, studies that utilize claims data to evaluate outcomes — or passive, such as voluntary adverse event reporting to the FDA.

The impact of the potential accumulation of antidrug antibodies are a major concern. One important question is if the loss of efficacy due to antidrug antibodies will be reported as an adverse event or categorized differently.

Regardless, clinicians should be encouraged to voluntarily submit adverse events, and to be mindful of correctly attributing the adverse event to the correct product.

To this end, the FDA has decided to utilize a four-letter suffix after a biological product’s “proper” name to distinguish the biosimilar and help clinicians correctly identify what product was administered. It is important to note that the FDA has not ruled on how to name interchangeable biosimilars.

Commitments to postmarketing pharmacovigilance programs may be mandated as part of the interchangeability determination, and they will be critical to confirming or negating the designation. Pharmacovigilance, of course, requires the input of clinicians, and correct attribution of adverse effects in order to be valuable.

PAGE BREAK

Substitution process

Within the medication use process — prescribing, dispensing and administration — the interchangeability designation plays a major role in that many state pharmacy practice laws allow pharmacists to independently substitute a biosimilar for the reference if it is designated as interchangeable by the FDA.

Twenty-six states have passed biosimilars substitution bills to this effect, with some stipulations similar to generic substitution laws. For example, prescribers would retain the ability to write “dispense as written” if they do not want a biologic substitution made, just as they do for a generic product.

However, there are some differences in the process:

  • Pharmacists are not able to legally substitute biosimilars for the reference product outside of obtaining a new prescription. If the prescription is written based on the reference product’s name, the patient’s out-of-pocket costs may be higher based on the patient’s insurance benefit design. Consequently, prescribers must specify which product should be dispensed to the patient.
  • If interchangeable biosimilars are available and the prescriber has no preference about the specific product given, the prescriber should write the prescription based on the reference product’s name so the pharmacist can decide which product will be dispensed.
  • If a prescriber has a specific product in mind — whether it is a biosimilar or reference product — the actual product’s name should be stated, with a note that substitution is not permissible.

These added steps are a departure from our experience with generic drugs.

Additional stipulations within these substitution laws aim to further facilitate pharmacovigilance and ensure patient safety by requiring the pharmacist to notify the prescriber when substitution occurs.

Formulary decisions for interchangeable biosimilars also will rely heavily on whether a product is deemed to be interchangeable.

It is important to note, however, that biosimilars with additional efficacy studies are not necessarily “better” or “more interchangeable” than other products. In fact, because efficacy studies are not required to determine interchangeability as per FDA regulations, clinicians should not expect these trials to be available for the majority of biosimilars, regardless of whether they receive interchangeability designation.

In contrast, the availability of clinical data of a particular biosimilar may sometimes be indicative of FDA concern.

Biosimilar companies may only conduct these trials if required by the FDA due to concerns about the comparison of quality attributes or pharmacokinetics/pharmacodynamics data between the biosimilar and reference product.

Overall, the biosimilar clinical drug development environment continues to evolve, and it will take time for clinicians and patients to become comfortable using biosimilars.

PAGE BREAK

We can draw on the experience of early adopters and of our colleagues in Europe, and our comfort level may be heightened as biosimilars products seek to achieve the formal designation as being “interchangeable.”

The expectations for biosimilars, and the policies related to the use of these agents, should balance cost considerations with scientific justification and the rigorous need for evidence.

As of press time, the FDA had not designated any biosimilars as interchangeable, and it may be some time before we see any.

Biosimilars themselves have been slow to make it to market. In hematology/oncology, the only FDA–approved biosimilar is filgrastim-sndz (Zarxio, Sandoz), a biosimilar of filgrastim (Neupogen, Amgen). Apobiologix is awaiting an FDA decision on its own biosimilar version for this same product.

The FDA also is reviewing applications submitted by Apobiologix, Coherus BioSciences and Mylan for biosimilars to pegfilgrastim (Neulasta, Amgen).

Hopefully, as the FDA provides more clarity on the pathways for biosimilars, these newer biologics will make it into the hands of clinicians sooner.

Reference:

FDA. Considerations in demonstrating interchangeability with a reference product: Guidance for industry. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/UCM537135.pdf. Accessed on May 5, 2017.

For more information:

Edward C. Li, PharmD, MPH, BCOP, is associate professor in the department of pharmacy practice at University of New England College of Pharmacy in Portland, Maine. He is a board-certified oncology pharmacist who maintains a practice with New England Cancer Specialists and develops cancer treatment pathways with New Century Health. He can be reached at eli@une.edu.

Disclosure: Li reports financial relationships with Apobiologix, Eli Lilly and Pfizer.

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