Greater uptake, education needed to realize cost-saving potential of biosimilars
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More than 5 years after the first FDA approval of a biosimilar, the U.S. health care system has yet to realize the full potential of these products to reduce drug costs and increase access to hematology/oncology treatments.
Biosimilars receive FDA approval after demonstrating no clinically meaningful differences in efficacy and safety compared with their patent-lapsed reference products. Because biosimilars — like generic drugs — are priced lower than their reference products, their introduction was predicted to drive down cancer costs by increasing competition.
Source: University of Colorado School of Medicine.
However, data suggest clinicians are not completely comfortable prescribing them. Further, there are no regulations mandating their use.
Still, experts with whom HemOnc Today spoke suggested 5 years is too short a time frame to evaluate the impact of biosimilars. If their use grows exponentially over the next decade, as predicted, it could lead to substantial savings and expand drug access to patients who otherwise may not be able to afford treatment.
“It’s too early to have a clear picture about what these are going to do down the road,” Gary H. Lyman, MD, MPH, FASCO, FRCP (Edin), senior lead in health care quality and policy, professor of the cancer prevention program and professor of the clinical research division at Fred Hutchinson Institute for Cancer Outcomes Research, told HemOnc Today. “The reason for my hesitation is that if you look at the European experience, there has been an impact, but they have a very different system than us. Here, we are behind the curve because of late development, and is too early to determine what impact biosimilars will have here.
“The U.S. has a very different health care environment,” he added. “People don’t want to be told what they can and can’t use, whereas health care in Europe is more regulated and they automatically had a much larger uptake in the use of biosimilars.”
HemOnc Today spoke with researchers about the development of biosimilars in the U.S., the impact their availability has had on drug costs so far, and how improved physician education is needed to expand use of biosimilars.
Introduction of biosimilars
Rising health care costs in the United States prompted the need for cost-containment strategies to help expand access and ensure patients received necessary treatments.
Biosimilars — highly similar versions of reference biologics with expired patents — promised to address these concerns. The Biologics Price Competition and Innovation Act, embedded in the Affordable Care Act, led to the creation of a regulatory pathway for biosimilars, which are regulated by the FDA differently than generics.
“This legislation came on the heels of the ACA, but biologics were already in the process of being developed and they had already gained a foothold in the rest of the world,” Lyman said. “The ACA made it more pressing that we rein in spending on these expensive drugs, but I think they would have been introduced regardless.
“There were two forces that made this inevitable,” he added. “One is that these are very complicated and very expensive medications. So, any way to drive down the price of these has been of interest at the national level. Secondly, like all medications, there is a patent life. As it expired — in some cases a couple of decades later — it led many companies to think that these are very expensive but very lucrative products.”
Although the European Medicines Agency approved the first biosimilar in Europe in 2006, it wasn’t until 2015 that the FDA approved the oncology supportive care product filgrastim-sndz (Zarxio, Sandoz) to decrease incidence of febrile neutropenia among patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs.
To date, the FDA has approved 28 biosimilars, 16 of which had indications for cancer.
“The first utilized biosimilar in oncology was not an anticancer therapy, it was for helping the body create white blood cells,” Jai N. Patel, PharmD, BCOP, CPP, chair of cancer pharmacology and pharmacogenomics at Levine Cancer Institute at Atrium Health, and a HemOnc Today Editorial Board Member, said in an interview. “It’s nice that it started with that drug because it’s lower risk than chemotherapy. Having filgrastim-sndz be the first-approved biosimilar in the U.S. provided some knowledge and comfort to providers for prescribing biosimilars prior to using them as highly toxic therapy that has a big effect on fighting tumors.”
Because biologics are complex molecules synthesized in living organisms, no two batches of biologics are completely identical and, therefore, biosimilars are not identical to their reference products.
“Generics are made with the exact same chemical synthesis as the name-brand drug, whereas biosimilars are highly similar with regard to efficacy and safety, but they are not identical to the reference drug,” Manali Kamdar, MD, associate professor of medicine in hematology, clinical director of lymphoma services at University of Colorado School of Medicine and CU Cancer Center mentored member, told HemOnc Today. “In order to get biosimilars approved, they have to undergo rigorous testing; you can’t just extrapolate information and data like you can with generics.”
However, the approval pathway for biosimilars requires far less patient-level clinical trial data than the reference drug. Instead, companies must present extensive preclinical information — such as pharmacokinetic and pharmacodynamic studies — to prove that the molecule will work as effectively as the drug it is trying to imitate.
“The FDA realized very early on that if they required extensive trial data for all of the biosimilars, they were never going to bring the price down because it could be more expensive to create than the original,” Lyman said. “So, they focused on developing these molecules based on analytic capability. They evaluate these molecules with every tool possible to make sure the biosimilars are precisely like the original biologic. In return for that, they require fewer large, randomized clinical trials, which saves money overall and leads to price reductions down the line.”
One problem, however, is that companies generally are developing biosimilars for common types of cancers, leaving patients with rare cancers with limited, more expensive treatments.
Trastuzumab (Herceptin, Genentech/Roche), for example, has five biosimilars for the treatment of certain types of breast and stomach cancers.
“From a company standpoint, there is an incentive to go after a type of cancer where there will be more sales and use, like breast cancer and colorectal cancer,” Patel said. “They also look at where the biologic patents are so that they can strike once those expire, getting the preclinical work done ahead of time. Companies are always looking down the road at that to see where the opportunities are.”
Potential for cost savings
Although they have been on the market for 5 years, biosimilars have yet to dramatically decrease the costs of drugs and cancer care in the United States.
However, experts say 5 years is not nearly enough time to properly analyze whether these drugs will achieve their intended purpose of bringing prices down, and they point to the next decade as critical for the future of these agents.
“The first 5 years was spent laying out the framework for how we want to approach using biosimilars. They weren’t used immediately after they were approved,” Patel said. “Now, we have a much more efficient process in how we approve and prescribe biosimilars. Because these processes are in place, we will see billions in savings over the next 10 years.”
Projections published in 2017 by Rand Corporation estimated that biosimilars would reduce direct spending on biologic drugs by $54 billion (range, 24-150) from 2017 to 2026, or about 3% of total estimated biologic spending over that period.
Researchers believe biosimilars could still meet that target.
“There was a lot of hype early on and right now we are in this middle phase of adoption,” Patel said. “I’m hoping we will see an exponential increase in biosimilar adoption over the next 10 years. If that happens, you will start to see huge benefits with costs.”
For instance, in a U.S. comparative cost-efficiency analysis presented during the ASCO20 Virtual Scientific Program, McBride and colleagues demonstrated that pegfilgrastim-cbqv (Udenyca, Coherus Biosciences) has the potential to significantly reduce the costs of chemotherapy-induced neutropenia and febrile neutropenia prophylaxis compared with reference pegfilgrastim (Neulasta, Amgen).
The researchers conducted simulation modeling from the U.S. payer perspective using the average selling price from the first quarter of 2020 CMS reimbursement limits for the reference and biosimilar drugs. The model simulated one to six cycles of prophylaxis in a panel of 20,000 patients with cancer at risk for chemotherapy-induced neutropenia and febrile neutropenia, with 10% to 100% conversion rates from the reference product to its biosimilar.
Using the average selling price at the time of the study, results showed a cost-savings per patient with the biosimilar ranging from $223 for one cycle to $1,335 for six cycles.
For the entire patient panel, savings ranged from $445,163 for one cycle at 10% conversion to $26,709,788 for six cycles at 100% conversion.
The researchers suggested that these savings could lead to reallocation of extra drug doses to provide more patients prophylaxis. Based on a single cycle of chemotherapy, researchers estimated that the savings would provide an extra 115 doses at 10% conversion and 1,154 doses at 100% conversion. When increased to six cycles, the additional doses ranged from 692 to 6,921.
“There is a potential for a 30% reduction in health care costs when it comes to using biosimilars,” Kamdar said. “That would eventually translate into increased access to a lot more patients. But have I actually seen this benefit in my field? Not yet.”
Biosimilar spending has doubled since 2017, but it still represents less than 2% of the total U.S. biologics market, Patel added.
Often there is a delay after FDA approval before price reductions will be realized. For example, it has taken filgrastim-sndz nearly 5 years to achieve a 32% share of the filgrastim market.
“In order to make a significant impact on the market, it was expected that there would be a significant price decrease,” Robert M. Rifkin, MD, FACP, clinical associate professor of medicine in the department of internal medicine at University of Colorado, told HemOnc Today. “When the first biosimilar appeared, there was an approximate 15% decrease in price. As a result of this initial offering, there was little uptake. However, over time with shifts in the market, a reasonable expectation is for biosimilars to enter the marketplace at a price 30% less than the originator molecule.
“For a biosimilar to enter the marketplace, the patent must expire on the originator molecule,” Rifkin added. “It is not uncommon for biosimilar manufacturers to start developing a biosimilar candidate molecule via reverse engineering 7 to 10 years prior to patent expiry.”
The biosimilar approval process usually is completed by the Biosimilar Regulatory Pathway. This allows the candidate biosimilar to be submitted with a data package that is considerably abbreviated from that of the originator. This data package relies heavily on analytics, and much less heavily on clinical trials. There is always a requirement for pharmacokinetic and pharmacodynamic studies. In addition, immunogenicity is thoroughly evaluated.
“These complicated molecules have many steps in the practices to manufacture, so this allows the original companies to get different patents on different aspects of the manufacturing and development of these agents,” Lyman said.
When this happens, companies can get caught in “patent dances” where the manufacturer of a biosimilar gets around one patent only to confront one or two more, he added. The result is a delay in getting approved biosimilars onto the market.
Lessons can be learned from the approval of generic drugs, Lyman said.
Generic imatinib, for example, was approved in 2016 but only began to lead to noticeable price decreases over the last 2 years, according to a talk Lyman gave in De`cember at ASH Annual Meeting and Exposition.
That decline came after steep increases in the price of the branded drug — which transformed treatment of chronic myeloid leukemia — and several years of expensive generic options.
However, the introduction of generics for branded imatinib (Gleevec, Novartis) did not initially bring down the price of the drug. In fact, the price of Gleevec continued to increase — the year Gleevec launched, the price was $40,000 per year for the standard dosing schedule. When the patent expired in 2013, it was $80,000 per year.
By the time generics came out, the price of Gleevec was close to $140,000 per year for a typical patient.
“One of the messages we learned from generics is that when they first came out, we saw very little impact on pricing,” Lyman said. “These generics are identical to the originator, and even then it has taken a few years for enough competition to build up to bring the prices down.
“That’s a lesson for biosimilars, which are much more complicated than the generics,” he added. “The U.S. is probably going to be slower to adopt these and slower to see a big reduction in pricing.”
The key to achieving the potential cost savings is greater uptake among clinicians.
“It is still a little bit early to know if it’s bringing down the cost, but what we have seen in the last 5 years is that product utilization has gone up,” Patel said. “The issue is that this is a novel aspect of drug development, and pharmacists and doctors are not well-equipped to understand how biosimilars are approved and how they work. The future is going to depend on the adoption of these drugs for regular use.”
Improving uptake
Education remains key to ensure pharmacists and clinicians have that understanding to improve uptake.
“Education of all stakeholders is extraordinarily important to ensure biosimilar adoption,” Rifkin said. “Not only do physicians require considerable education, but so do advanced practice providers and other stakeholders. Pharmacists and nurses require education in order to focus on all aspects of the patient journey.
“It is extremely important to ensure front office and back office support to minimize prior authorizations and decrease the hassle factors for patients and providers alike,” he added. “At the end of the day, the nurses are administering the biosimilar, and all must be confident and well-educated to effectively deliver them.”
But, once physicians become comfortable prescribing biosimilars instead of the brand names they have been using for years, demand will increase and prices will decrease, experts say.
Physicians who have been educated on biosimilars in their field are generally comfortable using them, Kamdar said.
“I personally prescribe biosimilars in my practice. For example, we frequently use [rituximab-pvvr (Ruxience, Pfizer)], which is our preferred [biosimilar to brand-name rituximab (Rituxan; Genentech, Biogen)] for management of B-cell non-Hodgkin lymphomas,” Kamdar said. “There are a couple of biosimilars available for growth factor support, as well, which we prescribe for patients going through intensive chemotherapy or at high risk for neutropenia and infection. We try to curb that risk by using the growth factor biosimilars.”
According to results of a cross-sectional survey of 75 hospital-affiliated and community-based oncologists conducted by Galan and colleagues, most of those surveyed still used branded drugs, with costs reported as a driving influence on whether biosimilars are prescribed.
The researchers surveyed oncologists about their use of biosimilars for bevacizumab (Avastin, Genentech), trastuzumab, rituximab and pegfilgrastim in July 2019.
Results, presented during the ASCO20 Virtual Scientific Program, showed 76% of the oncologists reported still using the branded drugs for these agents often or always.
However, 70% reported that they believe the biosimilars for these products were the same or near equivalent in quality to the branded drug. Sixty percent of providers reported that they would often or always prescribe biosimilars in the future.
Researchers found that the top drivers of biosimilar use were out-of-pocket cost to the patient (fee-for-service reimbursement, 61%; value-based reimbursement, 69%), value of reimbursement (51% and 44%) and cost to the practice (52% and 61%).
In addition to cost considerations, use of biosimilars typically is an institutional decision, Kamdar said.
“At the University of Colorado, our team has decided to move forward with using biosimilar growth factor supports to help save on costs,” she said. “Data exist showing that biosimilars for rituximab work just as well for B-cell lymphomas, so patients with B-cell lymphoma who need rituximab as a single agent or as part of their chemotherapy regimen will now use a biosimilar at our institutions.”
The endorsement of medical societies also is key, Patel said.
“A lot of us rely on opinions from national organizations like ASCO, National Comprehensive Cancer Network (NCCN), etc,” he said. “NCCN revising its guidelines this year on biosimilars to indicate that they are appropriate substitutes for FDA-approved biologics was very important. That will speak volumes in increasing adoption.”
Medical conferences also provide important opportunities to expand biosimilar education.
“We have focused our attention on getting on the agenda at major professional meetings,” Lyman said. “We are trying to educate our colleagues on the rigor of the process these agents go through before they are approved and that they are equally effective and safe.”
Post-marketing surveillance studies are key to provider education, Patel said, because these will help demonstrate why a biosimilar tested in breast cancer is then approved for four different cancers.
“That’s all part of the process of biosimilar development, and providers have to understand why that is,” Patel said. “The post-marketing evaluation is critical for the adoption of biosimilars in practice and to have providers be comfortable with the safety. Even though we may have not conducted a clinical trial for a specific indication, that post-marketing data on the use of the biosimilar are going to be very helpful.”
‘A wake-up call’
In addition to making providers feel more comfortable prescribing biosimilars, post-marketing studies have provided a check on how the originator products are performing.
Pivot and colleagues compared reference trastuzumab with one of its biosimilars, trastuzumab-dttb (Ontruzant, Merck), among 367 patients with early breast cancer.
Results, published last year in European Journal of Cancer, showed that after 3 years of follow-up, 91% of patients assigned the biosimilar achieved EFS compared with 85.2% of those assigned reference trastuzumab. Fewer patients assigned the biosimilar experienced an event (9.1% vs. 17.1%; HR = 0.47; 95% CI, 0.26-0.87).
“To the researchers’ surprise, the biosimilar actually worked better than the original agent,” Lyman said. “They went back and looked at original batches of Herceptin and found that some of the parameters had fallen off in recent batches. For instance, an antibody assessing the immunotherapeutic aspects of Herceptin had drifted below the threshold that the FDA had established for maintaining its efficacy. Batches that had no drift from the originator had the exact same efficacy as the biosimilar, but in batches where it did drift, those patients did not do as well.”
These data emphasized the importance of monitoring biologics over time, he added.
“It brought forth a lesson that these complex biologic agents are subject to changes in the components over time, and if they aren’t monitored very closely, they are subject to this drift and a loss of effectiveness,” Lyman said. “In this way, biosimilars made the originator better, and this was a wake-up call that we need to be very careful in monitoring these agents to make sure they’re working as they should.
“With all that in mind, I am very comfortable that biosimilars are just as safe and effective as the originators,” he added. “Even the originators today are not exactly the same drug they were 20 years ago as the company opens up new plants and uses new components and new sources of chemicals that go into manufacturing. There are slight changes that occur over time and it behooves us to keep checking that, and biosimilars can do that.”
Going forward, the COVID-19 pandemic may make biosimilars more relevant to health care, experts said.
“Research and development — as well as other aspects of health care — slowed down because of the COVID crisis,” Kamdar said. “[But] I think momentum will pick up again.
“Anything that reduces costs without compromising efficacy or safety is a welcome change, especially in the economy we are currently living in,” she added. “We are beginning to see that change happening in oncology, especially since 2018, when several biosimilars were approved by the FDA. I am more than happy to use biosimilars that are approved because they reduce costs and clinically reduce the burden of health care.
References:
Galan C, et al. Abstract e15213. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Lyman GH. The US experience with generic imatinib in CML: Did cost predictions meet reality? Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
McBride A, et al. Abstract e19372. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Mulcahy AW, et al. Rand Health Q. 2017;doi:10.7249/PE264.
Nabhan C, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.2004.
Pivot X, et al. Eur J Cancer. 2019;doi:10.1016/j.ejca.2019.07.015.
For more information:
Gary H. Lyman, MD, MPH, FASCO, FRCP (Edin), can be reached at glyman@fredhutch.org.
Jai N. Patel, PharmD, BCOP, CPP, can be reached at jai.patel@atriumhealth.org.
Manali Kamdar, MD, can be reached at manali.kamdar@ucdenver.edu.
Robert M. Rifkin, MD, FACP, can be reached at robert.rifkin@uchealth.org.
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