In a Roundtable Discussion held during the 2015 American Society of Hematology (ASH) Annual Meeting, several experts addressed questions related to biosimilar products and gauged the potential impact of these drugs on oncology care. These experts included Robert Rifkin, MD, FACP, Medical Director of Biosimilars, McKesson Specialty Health, The US Oncology Network, The Woodlands, Texas; Corey Cutler, MD, MPH, Associate Professor of Medicine, Harvard Medical School and Medical Oncologist, Dana-Farber Cancer Center, Boston, Massachusetts; Pere Gascón, MD, Chief of Medical Oncology, Hospital Clinic Barcelona, and Director, Laboratory of Molecular and Translational Oncology at CELLEX, Barcelona; and Mark McCamish, MD, PhD, Former Global Head,* Biopharmaceutical and Oncology Injectables Development, Sandoz, Inc. (*retired from Sandoz, Inc. in September 2016).
Their conversation is captured in this report.
What Is a Biosimilar?
A biosimilar product is a biologic agent that is highly similar to an already-approved biological compound, known as the reference or originator product, and approved for use in the same indications as the reference product. Biological products can be made of sugars, proteins, nucleic acids, or complex combinations of these substances, or may be living entities such as cells and tissues. According to the U.S. Food and Drug Administration (FDA), biosimilarity is confirmed when “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”2 For a biosimilar product to receive approval from the FDA, it must have the same mechanism of action, route of administration, dosage form, and strength as the reference product. Approval is granted only for the indications and conditions of use that have been approved for the reference product, though “extrapolation” to other indications can occur.
As such, the biosimilar agent filgrastim-sndz is approved for the same indications as the reference product, filgrastim (Neupogen): for patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia.
Simplifying the Definition
Biosimilar products remain a confusing entity to the health-care community. Robert Rifkin, MD, FACP, as moderator of the Roundtable, initiated the conversation by asking the faculty to describe their personal understanding of biosimilars, and to offer their simple, working definitions for these compounds.
…as a biosimilar sponsor we don’t aim to make a non-interchangeable biosimilar and then somehow change the molecule to make it interchangeable. We start out to make the highest-quality product that is essentially the same as the originator. It is a regulatory hurdle to provide the additional information required to provide the reassurance that switching is acceptable.— Mark McCamish, MD, PhD
According to Mark McCamish, MD, PhD, the definition that makes the most sense to clinicians is a compound that is designed to have essentially the same active pharmaceutical ingredient as the reference product and that can be clinically applied exactly as the reference product is used. Corey Cutler, MD, MPH, a clinician, said he thinks of biologics as “the equivalent of generics, but in the biological space,” acknowledging that they are more difficult to reproduce “as a true exact copy” than generics. “But we all are used to the concept of a generic drug, which is just like the originator drug… so I like to think of these drugs as essentially generics for the biologic originator product,” he said.
Pere Gascón, MD, a European oncologist, preferred not to use the term “generic,” but agreed that a biologic is “essentially highly, highly similar” to the originator and demonstrates “the quality attributes of the originator.” By being subjected to most of the same chemical and physical processes as the reference product, a biosimilar is “as equal as it can be to the originator from the structural and clinical points of view,” he said.
What Is the Regulatory Process for Biosimilar Approval?
The FDA approval of a biosimilar follows the 351(k) pathway, an abbreviated new drug application (ANDA) process created by the Biologics Price Competition and Innovation Act of 2009, which was part of the Patient Protection and Affordable Care Act. This pathway leads the molecule through a comprehensive set of exercises and evaluations to prove it is not meaningfully different from the reference product. The approval process for biosimilars is stepwise, and the extent and nature of data for each step depends on the level of support obtained in the preceding step.
“Regulators want evidence to show that the biosimilar is essentially the same as the reference product, which includes analytical information—its chemical structure and its function in terms of the biologic activity,” Dr. Rifkin said. The preclinical and clinical information comprise what FDA regulators label the “totality of evidence,” which is aimed to prove the biosimilar is essentially the same as the reference product. “It’s built on a whole cascade of information,” Dr. Rifkin said.
The goal in development is to show a high degree of similarity to the reference drug. Comparability is established from analytical studies (structure, function, receptor binding, and so forth) and in vivo tests in animals and humans. An examination of the biosimilar’s pharmacokinetics, within predefined equivalence margins, is the first step toward its approval.
Based on pharmacokinetic and other analytical studies showing similarity, the clinical evaluation can sometimes be abbreviated. In humans, investigators evaluate pharmacodynamics, pharmacokinetics, and immunogenicity and perform comparative studies in the most appropriate clinical setting. A noninferiority clinical trial, usually conducted in the most “sensitive” population, requires that similarity in pharmacokinetics and pharmacodynamics be shown only in the most relevant clinical indication, though the compound can have multiple approved indications.
If there has been a large enough clinical trial—for example, staying with rituximab, let’s say in chronic lymphocytic leukemia—and if the biosimilar is proven in that clinical trial to have essentially the same clinical activity, then I think we have no choice but to extrapolate that the drug will work in follicular lymphoma, mantle cell lymphoma, and large cell lymphoma, which are all disorders of malignant B cells.— Corey Cutler, MD, MPH
According to a review article by Rugo et al, “The clinical program is not to demonstrate clinical efficacy per se, as this was established for the reference product, but to address any residual uncertainty about biosimilarity after conducting physicochemical and biological characterization and, where appropriate, animal studies.”3 Clinical outcomes do not need to be proven—but the drug must show that its clinical activity is not different from the originator. Favorable results on all these processes, along with assurances of safety, usually will be sufficient criteria leading to FDA approval, although the FDA may ask for more data or recommend against approval.
Even with 10 years of experience with biosimilars in Europe, the EMA, along with various clinical congresses and societies there, have struggled to differentiate biosimilars from biologics and generics in terms that physicians and the public will understand. How alike and how different are these compounds? “It’s an unfortunate term—biosimilar—because when a physician hears it, what he or she understands is ‘bio-different,’” Dr. McCamish said. “You can’t say ‘bioidentical’ because biologics, whether the reference product or biosimilar product, vary slightly [among themselves].” The term “biosimilar,” should communicate that you are using essentially the same active ingredient of the reference product—like using a different batch of the reference product,” he suggested.
Dr. Rifkin indicated here that “biosimilar” is a regulatory term and not a drug name, per se.
Even the reference product is not an identical copy of itself, due to batch-to-batch differences in manufacturing over time. These differences are due to the inherent variability of the biological expression system and the manufacturing process. Despite the potential for some small degree of variability in the manufacturing of both biologics and biosimilars, said Dr. Cutler, “They are all within a very, very tight window of physicochemical properties, such that they really are meaningfully the same.” Dr. Gascón agreed, noting, “The definition for the biosimilar is for a drug to be as close as possible to—or essentially the same as—the originator.”
Selected Thoughts From the Faculty
What Is a Biosimilar?
According to Dr. McCamish, the definition that makes the most sense to clinicians is a compound that is designed to have essentially the same active pharmaceutical ingredient as the reference product and that can be clinically applied exactly as the reference product is used. Dr. Cutler, a clinician, said he thinks of biologics as “the equivalent of generics, but in the biological space,” acknowledging that they are more difficult to reproduce “as a true exact copy” than generics. “But we all are used to the concept of a generic drug, which is just like the originator drug… so I like to think of these drugs as essentially generics for the biologic originator product,” he said.
Dr. Gascón, a European oncologist, preferred not to use the term “generic,” but agreed that a biologic is “essentially highly, highly similar” to the originator and demonstrates “the quality attributes of the originator.” By being subjected to most of the same chemical and physical processes as the reference product, a biosimilar is “as equal as it can be to the originator from the structural and clinical points of view,” he offered. ■
Dr. McCamish pointed out that, since biologics are made by living cells, they must mirror the natural occurrences in the human body. For example, erythropoietin produced in the body can have different glycosylation patterns, ie, isoforms. “This tells you that variability is allowed in the biologic space,” he said. “It’s just a natural phenomenon.” In the production of a pharmaceutical product, variability in composition must be controlled within a very narrow range. The narrow range required for the originator is what is replicated for components of the biosimilar.
“The biosimilar has to have the identical amino acid structure as the originator. So, the protein is identical. The amino acid structure, the folding, and the primary, secondary, and tertiary structures have to be identical. It’s just the post-translational modification where the originator varies and then the biosimilar has to be shown to vary similarly,” Dr. McCamish explained. He further pointed out that due to advances in biotechnology, the manufacturing of reference products has improved over time, but companies that improve upon their products must demonstrate that these improvements have not significantly altered their drug. Should there be any changes, manufacturers of biosimilars would have to match those physical, chemical, and structural properties, he said.
The stated goal for biosimilar manufacturing is to produce a product that is “as close to the originator as the originator is to itself, considering that the originator changes with each batch, as manufacturing changes. The goal is to have this essential ‘sameness,’” Dr. McCamish said.
Interestingly, according to Dr. Cutler, there can be no intention of improving upon the original product. “Even if you can make that biosimilar better or more uniform, the goal is really to overlap or mimic the originator’s range,” he pointed out. Dr. McCamish further noted that while it would be possible to refine the molecule, for example, to make it more bioavailable, this would change its pharmacokinetic capability, and that is not allowed. In other words, the inherent function of the original biologic must be maintained.
Dr. Gascón agreed. “Remove the impurities and you have a new product, but then it’s not a biosimilar. We have this paradox in that we are now able to highly purify the biosimilar to make it even better, but then if it is better, it will not be a biosimilar.” Ultimately, Dr. McCamish suggested, oncology providers can understand biosimilars through the concept of “sameness,” which is essentially applied to both generics and biosimilars, even though their precise definitions and regulatory processes are different, he said. “Yes, even if you can make that biosimilar better or more uniform, the goal is really to overlap or mimic the originator’s range,” Dr. Cutler added.
Clinical Trials of Biosimilars
Dr. Rifkin initiated a discussion of clinical trials of biosimilars—the final step of the regulatory process. Accrual to these noninferiority trials has typically been less robust than accrual to phase III trials of reference biologics. He asked the panelists for their thoughts on these differences.
In Dr. Cutler’s clinical experience, he indicated that patients are most interested in clinical trials offering the potential of improved therapeutic efficacy vs the standard of care. Biosimilar trials, while important for proving safety, may not be as attractive to patients since “the best patients can hope for is to get the same thing they are getting now,” he said.
“These trials are exceptionally important but they don’t have the same attraction as a trial of a novel agent,” Dr. McCamish agreed. Since biosimilar trials are meant to confirm the efficacy shown for the reference product, they simply guarantee that every subject receives the “appropriate” treatment. “Because of the difficulty with enrollment, we sometimes have to go to regions where there is a problem with drug access or cost…where the incentive for patients to be involved is to avoid a copayment for either the originator drug or the biosimilar [which is covered by the sponsor],” he added. “[The sponsor is] not only paying to conduct the trial, but [also] buying the originator product for patients randomized to that arm. It’s very expensive.”
Selected Thoughts From the Faculty
“Extrapolation” is the term that describes the use of a biosimilar in all indications of the reference product when the clinical trial used for approval was performed in less than all indications of the reference product. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory guidelines allow extrapolation when it appears scientifically justified and the totality of evidence demonstrates the biosimilarity of the drug and its known mechanism of action.
“One has to be open to the idea of extrapolation,” Dr. Cutler said. “If there has been a large enough clinical trial—for example, of rituximab (Rituxan) in chronic lymphocytic leukemia—and if the biosimilar is proven in that clinical trial to have essentially the same clinical activity as the reference product, then I think we have no choice but to extrapolate that the drug will work in follicular lymphoma, mantle cell lymphoma, and large cell lymphoma, which are all disorders of malignant B cells,” he said. “I don’t think we can ask the manufacturers of the biosimilar products to seek labels for every one of these disease indications. If the drug is the same [as the originator product] in one malignant B-cell disease, then it’s going to be the same in all of the malignant B-cell diseases.” ■
In Europe, according to Dr. Gascón, the situation is very different, and interest among patients is greater. Despite lacking a financial incentive for participation (ie, government-run health-care systems do not involve copays), and understanding that the treatment arms are assumed to be equally effective, approximately 20% of eligible patients in Spain enroll. Patients are encouraged to help evaluate drugs in order to “advance oncology or help bring down prices…. People just participate,” he reported.
How Is a Biosimilar Different From a Generic?
The FDA defines a generic drug as a compound that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality, performance characteristics, and intended use; it must also show bioequivalence to the branded drug, that is, demonstrate a rate and extent of absorption that is not significantly different or, if it is, has differences that are not intentional and are not medically significant.4 As Dr. Cutler suggested, the term “generic” implies that drugs are “actually identical” and that “100% of the time they are the same physical molecule,” but this cannot be said for biosimilars.
Generics are small-molecule compounds that have relatively simple structures. Because of this, they can be chemically synthesized with exactness in the laboratory to completely resemble the original compound. The recently approved complex generics like enoxaparin and glatiramer acetate are mixtures of various sizes of molecules, so it is not possible for the sponsor to make an identical single-molecule copy of the reference product, as it doesn’t exist. Sameness for these complex generics was established by showing among other things that the distribution of the molecules of the generic was the “same” as that of the reference product. “Sameness” was established, but an identical molecule could not be established. This is analogous to biosimilars. Although biologics, like complex generics, are difficult to characterize,5 it is possible with current techniques to characterize the physicochemical and functional attributes sufficiently to establish this “sameness” to satisfy the FDA if a biosimilar is approved.
What’s in a Name?
The naming of biosimilars is considered by some to be important for postmarketing pharmacovigilance, a system that monitors the safety of medicinal products and detects changes to their risk:benefit balance. The aim is to be able to differentiate the specific product a patient has received, especially when there are safety concerns. There has been considerable debate about the best approach to naming.
In its Draft Guidance issued in 2015, the FDA stated the following: “FDA’s current thinking is that a proper name that includes a designated suffix is warranted for biological products newly licensed and products previously licensed.”6 In other words, the biosimilar would have the same international nonproprietary name as its reference product because the active ingredient is the same; a random four-letter “biological qualifier” suffix would be added for distinction. This is intended to allow health-care systems, clinicians, and patients to differentiate between products, while adhering to the expectation that the products are indeed similar.
As the Draft Guidance stated, this approach should help “prevent a patient from receiving a product different from what was intended to be prescribed; facilitate manufacturer-specific pharmacovigilance by providing a means of determining which biological product is dispensed to patients; encourage routine use of designated suffixes in ordering, prescribing, dispensing, and recordkeeping practices for these products; and advance accurate perceptions of biological products.”
Selected Thoughts From the Faculty
Importantly for U.S. physicians, pharmacists can substitute an interchangeable product for the reference product without the intervention of the health-care provider who prescribed the reference product, a practice termed “automatic substitution.” The Panel offered some thoughts on this practice.
Dr. McCamish indicated, “Interchangeability is a different regulatory term and it is a higher standard for evidence, but the molecule is the same. So, for example, as a biosimilar sponsor we don’t aim to make a non-interchangeable biosimilar and then somehow change the molecule to make it interchangeable. We start out to make the highest quality product that is essentially the same as the originator. It is a regulatory hurdle to provide the additional information required to provide the reassurance that switching is acceptable.”
“From an FDA point of view,” Dr. Cutler added, “interchangeability has a very, very strict definition; it means that you can go from one compound to the other between cycles and repeatedly back and forth without a meaningful difference, and it is a very high bar to attain from a biosimilar manufacturer’s point of view.”
“My problem is that I want to know what I have in my pharmacy,” Dr. Gascón said. “I think physicians should not be kept out of the loop; we should at least know what drugs our patients are going to receive.” ■
Several industry groups—the Biosimilars Forum, PhRMA, and BIO—have supported the FDA’s proposal, but called for the agency to use “meaningful” and “distinguishable” suffixes linked to the license-holder’s name, as was done for the only U.S.-approved biosimilar from Sandoz, known now as Zarxio (filgrastim-sndz).7 However, critics of the FDA’s proposal have maintained that using a different or modified international nonproprietary name will actually make identification of drugs more difficult, and have argued for using the brand name for giving biosimilars names distinct from the reference product. The Generic Pharmaceutical Association’s Biosimilars Council and several insurers, including the Kaiser Foundation, CVS Health, and America’s Health Insurance Plans, are among those opposed to the proposal and who have suggested other measures for distinguishing biosimilars to enhance pharmacovigilance.
The panelists acknowledged the complexity surrounding the naming of biosimilars. As Dr. McCamish said, “One has to know that there are many forces on the table.” In the discussion, Dr. McCamish noted there are seven branded formulations of recombinant human growth hormone with the nonproprietary name of somatropin, without a suffix. “That’s been fine for years,” he commented.
“In Europe, the regulators are very content with using the same international nonproprietary name because the brand differentiates the product and you have multiple types of ways of tracking.” For example, there are nine biosimilar filgrastim products with different brand names. Dr. McCamish maintained that with the international nonproprietary name, the brand name, the batch number, and the J codes, there are sufficient processes already in place for identifying the product a patient has received.
As requested by the FDA, he said that Sandoz added the four-letter suffix “sndz” to nonproprietary filgrastim. “But everywhere else in the world, it’s just ‘filgrastim,’” he said. “From our perspective, a suffix is not necessary scientifically. We have provided data that says the biosimilar is essentially the same as the reference product, and then we change the name of the active pharmaceutical ingredient, the international nonproprietary name? To us, it just adds a layer of complexity that doesn’t help and it confuses the pharmacist and the physician,” Dr. McCamish said. He further suggested that existing technology—especially barcodes—could be better utilized in pharmacovigilance as a means of tracking and tracing products.
Concept of Extrapolation
The Roundtable participants discussed the concept of “extrapolation,” which occurs when a biosimilar is approved based on a clinical trial conducted in only one approved indication of the reference product, but is approved in all indications of the reference product. The FDA and EMA regulatory guidelines allow extrapolation when it appears scientifically justified and the totality of evidence demonstrates the biosimilarity of the drug and its known mechanism of action.8,9 The participants of this Roundtable agreed that a molecule proven to be the “same” as a reference product should function similarly and be acceptable in all the indications of the reference compound. They expect physicians, therefore, to leverage the data from one indication to support their use of a biosimilar in another indication. As an example, biosimilar rituximab may be approved for rheumatoid arthritis but could also be used by oncologists to treat non-Hodgkin lymphoma.
“One has to be open to the idea of extrapolation,” Dr. Cutler said. “If there has been a large enough clinical trial—for example, staying with rituximab, let’s say in chronic lymphocytic leukemia—and if the biosimilar is proven in that clinical trial to have essentially the same clinical activity, then I think we have no choice but to extrapolate that the drug will work in follicular lymphoma, mantle cell lymphoma, and large cell lymphoma, which are all disorders of malignant B cells,” he said. “I don’t think we can ask the manufacturers of the biosimilar products to seek labels for every one of these disease indications. If the drug is the same [as the originator product] in one malignant B-cell disease, then it’s going to be the same in all of the malignant B-cell diseases.”
The more physicians use these drugs, the more confidence they develop in them, and this has resulted in tremendous cost savings in each country. I think as physicians become more familiar with biosimilars and use them more, they see the safety and the economic advantages. It just takes a little time.— Pere Gascón, MD
Dr. McCamish questioned, however, whether the mechanism of actions would differ for drugs when used in unrelated conditions, and whether this would matter. “In rheumatoid arthritis, the mechanism of rituximab pertains to essentially healthy B cells, so does that compound work the same in cancerous B cells?” he asked. “I think the regulators are requesting rheumatoid arthritis data and oncology data as well, but not for all oncology indications.”
The participants acknowledged, however, that despite “sameness,” minuscule changes in various components of compounds could conceivably impact efficacy. For example, as Dr. Gascón described, rituximab exerts its antitumor effect through antibody-derived cytotoxicity, which is dependent on the content of fucose (a simple sugar), bound to monoclonal antibodies; monoclonal antibodies with a low fucose content exhibit high antibody-derived cytotoxic activity.9 Batches of rituximab can apparently vary in fucose levels and therefore perhaps in antibody-derived cytotoxic activity, but such variation can now be identified with great accuracy, Dr. Gascón indicated. Cell lines that are impotent and likely to produce suboptimal molecules can therefore be identified upfront. “We can be sure that when we have the end-product, we have high antibody-derived cytotoxicity,” he said.
Dr. McCamish said that these small changes in manufacturing both the reference product and the biosimilar, which naturally occur over time, should not lessen clinicians’ confidence in biosimilars. Sponsors must report any changes observed during manufacturing and demonstrate to authorities that they are not clinically relevant. When such changes are identified, regulatory authorities may require that a biosimilar be compared to the originator in a clinical trial, to confirm “sameness.”
“I want to reassure clinicians that from a manufacturing perspective, for the originator as well as the biosimilar, that there are controls that are enforced in order to produce a compound that is acceptable,” he stated.
Concept of Interchangeability
The FDA guidance also includes the concept of “interchangeability,” which refers to the substitution of a biosimilar for its reference product with the expectation of achieving the same clinical outcome as the originator in any patient in a given clinical setting. Patients who alternate between biosimilars and biologic reference products must be deemed to be at no greater risk, in terms of safety and efficacy, than that incurred by using the reference product alone.10
Because of confusion over terminology, the European Commission produced a consensus document that defines the terms as follows1:
Interchanging: the medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient on the initiative, or with the agreement of the prescriber
Substitution: the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber.
Switching: the decision by the treating physician to exchange one medicine for another medicine with the same therapeutic intent in patients who are undergoing treatment.
Importantly for U.S. physicians, an interchangeable product may be substituted for the reference product without the intervention of the health-care provider who prescribed the reference product, a practice termed “automatic substitution.” While the FDA will determine which biosimilars may be interchangeable (if that is the sponsor’s wish), it is up to each state to decide whether to allow automatic substitution. More than half the states have considered such legislation, but not all have passed laws that would allow automatic substitution.5 In Europe, interchangeability is determined not by the EMA but by each individual country.
As Dr. McCamish indicated, “Interchangeability is a different regulatory term and it is a higher standard for evidence, but the molecule is the same. So, for example, as a biosimilar sponsor we don’t aim to make a noninterchangeable biosimilar and then somehow change the molecule to make it interchangeable. We start out to make the highest-quality product that is essentially the same as the originator. It is a regulatory hurdle to provide the additional information required to provide the reassurance that switching is acceptable.”
“From an FDA point of view,” Dr. Cutler added, “interchangeability has a very, very strict definition; it means that you can go from one compound to the other between cycles and repeatedly back and forth without a meaningful difference, and it is a very high bar to attain from a biosimilar manufacturer’s point of view.”
Will Physicians Accept Interchangeability?
“My problem is that I want to know what I have in my pharmacy,” Dr. Gascón said. “I think physicians should not be kept out of the loop; we should at least know what drugs our patients are going to receive.”
Dr. Cutler agreed with the need for transparency, regarding automatic substitution, but commented, “I think we lost absolute control as physicians very long ago. We are subject to oversight by our own Pharmacy and Therapeutics Committees who decide which formulation is on our pharmacy shelves. And when we’re prescribing these agents in the outpatient setting, we are at the mercy of the payors who often will mandate a substitution, or put the onus of payment on patients for one product over the other.” He acknowledged that such restrictions do have value in terms of cost-containment.
The faculty agreed that interchangeability could create confusion in the clinic, and felt that their patients would prefer to see the same drug arrive each month from the pharmacy. “If my patient receives a box that is blue and 3 weeks later gets a box that’s yellow, he’s going to think that there’s a problem,” Dr. Gascón said. “It means I have to give a lot of explanations. So, for me it will be better if the patient starts with blue, no matter the brand or the four-letter suffix, and continues with the blue box to prevent confusion.” However, with proper education patients will adjust, the faculty predicted. “I think the four-letter suffix could actually be an entrée into the conversation with the patient,” Dr. Cutler said, “where the physician would say, ‘Yes, this is slightly different than what you received last month, but here’s why this drug is safe and is going to be equally efficacious for you.’ It might be a way for us to enter that conversation when the patient unexpectedly receives a different product than I might have initially intended or prescribed for them.”
Continuing the conversation about physician adoption of the novel agents, Dr. Rifkin said he had noticed that filgrastim-sndz is often just “sitting on the shelf.” This suggested to him there may be a lack of enthusiasm for the country’s first-approved biosimilar, and he asked the participants their thoughts on this question. Dr. Cutler pointed out that especially in the case of bulk purchasing, decisions are made on a level beyond the individual clinic. “There are often bigger forces at play,” he said. For example, it may be simply a matter of time before a drug becomes approved by the Pharmacy and Therapeutics Committee and its use “trickles down” to the individual practitioner, he said.
We will have many new molecules in a very short period of time. The workload at the FDA is quite high: they have more than 50 projects going on in biosimilars right now. It is our hope that patients and all stakeholders will reap the benefits of these efforts.— Robert Rifkin, MD, FACP
Indeed, this appears to have been the case in the European Union. According to Dr. Gascón, the uptake of biosimilars was initially sluggish throughout Europe, but their use solidly increased as physicians became accustomed to the drugs. Biosimilar filgrastim now outsells the originator in some countries, including the United Kingdom, he indicated. “The more physicians use these drugs, the more confidence they develop in them, and this has resulted in tremendous cost savings in each country. I think as physicians become more familiar with biosimilars and use them more, they see the safety and the economic advantages. It just takes a little time.”
Dr. McCamish said he is encouraged by the growth of the biosimilar segment in Europe, as it affirms a “vision” held in the United States—that biosimilars will improve patient access to the best drugs while also reducing the high cost of drugs that has been an impediment to contemporary cancer care. It is estimated that price reductions for biosimilar monoclonal antibodies could be as much as 50% that of the reference products.11,12
“In Europe, biosimilar filgrastim use has risen by close to 40% since 2009. More patients are being treated appropriately and the cost to the countries is actually less than with the originator. In the United States that’s a wonderful example of what can happen—though we can expect adoption to be a little slow initially,” Dr. McCamish continued. Dr. Rifkin agreed, “We need to increase patient access and we need to hold down costs, and I believe we see that happening in Europe.” Dr. Rifkin also noted that in Europe, patients accept biosimilars simply because their physicians prescribe them; therefore, physician buy-in will be critical.
Safety Profiles and Biosimilars
Obviously, the safety of any new product is a chief concern for physicians and patients. Dr. Rifkin asked how providers can assure patients that biosimilars have been proven safe as well as effective.
Much of the assurance comes from that fact that the reference product has been on the market for decades, the participants agreed. “It’s about their inherent sameness. There’s a huge safety database for the biologic that is being copied, and it is essentially the same product,” Dr. McCamish said. Information from large clinical trials of the originator, confirmed by data from the clinical trials of the biosimilar, resting upon a background of “sameness” between the molecules—this provides evidence of safety, he maintained.
“You can show patients the literature. You can print out published studies,” agreed Dr. Cutler, who added that his patients question the efficacy of biosimilars more than their safety. Dr. Gascón added that he is confident in the ability of pharmaceutical companies to manufacture a safe product. “Big names, with years of credibility, state-of-the-art technology, with oncologists behind that—to me this is very important, and it is a major point to make with our patients,” he commented. Strict regulations by the EMA have assured him of the highest quality for these products, he added, reporting that he has no trouble “putting his name on” prescriptions for compounds that are equally effective and more affordable.
Postapproval safety monitoring, ie, “pharmacovigilance,” will be important for biosimilars, experts in the field have agreed. As Rugo et al discussed, “Immunogenicity is a key element in establishing biosimilarity between the proposed biosimilar and the reference product and is assessed in both nonclinical and clinical studies. However, clinically meaningful immune responses to a biological agent may develop after long-term use, with the potential to affect both the safety and efficacy of the agent…. The clinical safety of all biological products, including biosimilars, must be monitored on an ongoing basis during the postapproval period of use. This will enable the identification of rare but potentially serious safety risks (eg, immunogenicity) not detected during the shorter follow-up of clinical studies.”3
How Do We Explain Biosimilars to Patients?
A challenge for oncologists will be to introduce these new compounds to their patients. “Our patients have been a bit left out of the discussion of biosimilars, but they are major stakeholders. How will we educate them that a biosimilar is not the originator, and how will we explain why we selected it for them?” Dr. Rifkin asked the faculty. He was remembering his own experience with generic drugs: patients had trouble accepting generic versions of warfarin and levothyroxine. “I think you have to explain to patients, in a reasonable manner, biosimilar’s sameness to the reference product,” he said. “The hardest part is differentiating drugs that are essentially the same.”
Dr. Rifkin believes that concerns about safety can be addressed through patient education, and that concerns about drug costs, especially among patients whose copays are prohibitive, are partially answered by biosimilars. Their introduction, he suggested, sends a positive message—that the pharmaceutical industry is responsive to issues of cost and is offering a potential solution.
Dr. Gascón felt that U.S. patients will ultimately become like their European peers, who seem to have embraced the idea of biosimilars for many reasons. For one thing, he said, the “financial crisis” in Europe convinced them of the need for lower-cost agents. But mainly, he added, “Patients trust their doctors to know what is good for them.”
Dr. Rifkin concluded the Roundtable by noting that the topic of biosimilars “will assume incredible importance going forward, as we seek to control cost and increase access to biologics…. We will have many new molecules in a very short period of time. The workload at the FDA is quite high: they have more than 50 projects going on in biosimilars right now. It is our hope that patients and all stakeholders will reap the benefits of these efforts. ” ■
Disclosures: Robert Rifkin, MD, FACP, has served on the Advisory Board of Sandoz, Amgen, Pfizer, Hospira, and EMD Serono. Corey Cutler, MD, MPH, has served as a consultant for Sandoz. Pere Gascón, MD, has served as a consultant for Sandoz. Mark McCamish, MD, PhD, was Global Head, Biopharmaceutical and Oncology Injectables Development for Sandoz, Inc. He retired from Sandoz, Inc. in September 2016.
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To watch a recording of the "Biosimilars in Oncology" Roundtable Discussion, visit http://www.ascopost.com/videos/ and search "Biosimilars Roundtable"