April 15, 2024
11 min read
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The age of biosimilars has come for gastroenterology. This includes interchangeable products, three of which are now on the market. How this will impact patient care in the near and distant future is the subject of much speculation.
While an increasing number of gastroenterologists and their patients have become familiar with the concept of biosimilar interchangeability, understanding is not universal among patients and practitioners.
“The rollout of three interchangeable biosimilars has several implications for patients. Most important would be improved access to biologics with reduced treatment expense.”
Source: NYU Langone Health
“An interchangeable biosimilar may be substituted at the pharmacy for the reference product without the intervention of the prescribing health care provider — much like how generic drugs are routinely substituted for brand-name drugs,” Miguel Regueiro, MD, chief of the Digestive Disease Institute at Cleveland Clinic, said in an interview. “This means that the prescriber and the patient may not know if the order for the reference biologic is being substituted for a biosimilar. A biosimilar is simply the medication but is not necessarily interchangeable unless it has that designation.”
Unlike in rheumatology, where multiple biosimilars have multiple indications, inflammatory bowel disease is currently the only gastrointestinal condition for which biosimilars are used. The three interchangeable products currently available include Cyltezo (adalimumab-adbm, Boehringer Ingelheim) and Abrilada (adalimumab-afzb, Pfizer), as interchangeable biosimilars to Humira (adalimumab, AbbVie), and Wezlana (ustekinumab-auub, Amgen) as an interchangeable biosimilar to Stelara (ustekinumab, Janssen).
“The rollout of three interchangeable biosimilars has several implications for patients,” Jordan Axelrad, MD, MPH, director of clinical and translational research at the Inflammatory Bowel Disease Center at NYU Langone Health, said. “Most important would be improved access to biologics with reduced treatment expense.”
Sarah Yim
Whether interchangeable biosimilars will truly lead to cost savings for patients remains to be seen. “Hopefully, the availability of both biosimilar and interchangeable biosimilar products will increase patient access to biologic medications and reduce their out-of-pocket costs,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA, said in an interview. “However, the pharmaceutical marketplace is complex — especially specialty pharmacy products, which applies to most biological products. There are only a few interchangeable products available to be substituted at the pharmacy level, so there is limited information about how they are impacting the market in terms of pricing.”
Stephen B. Hanauer
As cost issues evolve, the next challenge for gastroenterologists pertains to doctors and patients becoming familiar with biosimilars and the concept of interchangeability. “The concept of interchangeability is actually not important anymore since third-party payers can switch to less expensive biosimilars at their discretion,” Stephen B. Hanauer, MD, Clifford Joseph Barborka Professor of Medicine at Northwestern University Feinberg School of Medicine, told Healio Gastroenterology. “All biosimilars are de facto interchangeable since choice is no longer up to the clinician or patient.”
That said, Hanauer noted that uptake and understanding of biosimilarity and interchangeability remains a challenge in gastroenterology. “GI is lagging behind hematology/oncology and rheumatology, where biosimilars have been available for longer periods of time,” he said.
David P. Hudesman
Other experts see it differently. “The uptake of infliximab biosimilars has been universal for GI practices,” David P. Hudesman, MD, co-director of NYU Langone Health’s Inflammatory Bowel Disease Center, told Healio Gastroenterology. “These are the first biosimilars approved for inflammatory bowel disease. I believe gastroenterologists are very comfortable prescribing biosimilars, given their past experiences with infliximab.”
Lag or no lag, gastroenterologists’ comfort with an uptake of interchangeable products may be improved by the increasing availability of citrate-free versions of these medications. “If choice is permitted, many providers may opt for citrate-free options, which cause less pain on injection, or the originator product, based on known patient and provider support programs,” Axelrad said.
Education can improve all facets of uptake and use, according to Axelrad. “Providers may need to ensure that patients are informed about the similar safety and efficacy of interchangeable biosimilars,” he said. “Patients may also notice that biosimilar injectable devices and contents differ from the originator product, and providers may need to further train other providers and educate patients on the use of these new devices.”
More biosimilar and interchangeable products are likely to hit the market in the coming years. Clinicians should be armed with as much knowledge as possible to optimize their use in the clinic and stay ahead of patient concerns.
Efficacy Concerns ‘Unwarranted’
“We hear from stakeholders — including physician and patient groups — that there is confusion about interchangeable biosimilars,” Yim said. “There are concerns that biosimilars are not as safe or effective as the reference biologic or that an interchangeable biosimilar is better than a biosimilar that is not interchangeable.”
Yim described these concerns as “unwarranted” and stressed that they may discourage both physicians and patients from utilizing interchangeable medications. “They may also have concerns about switching to a biosimilar when both biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval,” she said. “It is important to note that both are as safe and effective as the reference biologic. As use of biosimilars becomes more common, we hope to see comfort levels increase, and we continue to create and update educational materials to help people become more familiar and comfortable with fundamental concepts about biosimilar and interchangeable products.”
Data show that this comfort may be increasing.
Cardinal Health recently released the 2023 Biosimilars Report, a publication outlining information pertaining to biosimilar uptake, along with perceptions and market trends. Results of the survey, which included 350 providers from various specialties, showed that 81% of gastroenterologists were “very familiar” with biosimilars.
Maia Kayal
“GIs are becoming more comfortable with prescribing interchangeable biosimilars,” Maia Kayal, MD, MS, assistant professor of gastroenterology at the Icahn School of Medicine at Mount Sinai and the Susan and Leonard Feinstein Inflammatory Bowel Disease Center, told Healio Gastroenterology. “We have reassuring data regarding reference to biosimilar switches, biosimilar to reference switches, and even biosimilar to biosimilar switches.”
Data in support of the efficacy of interchangeables are not limited to physician surveys. In a paper published in the Journal of Clinical Medicine, Ribaldone and colleagues assessed the impact of switching from biosimilar adalimumab to another biosimilar in a real-world setting. Multiple switches were evaluated in the analysis, which included 61 patients. Results at 6 months showed that 82% of the group reported success, which was defined as no systemic corticosteroids within that time period, non-discontinuation of the medication to which they switched and no dose escalation. The only predictor of switch failure was C-reactive protein levels higher than 5 mg/L, according to findings.
“The data supports no differences in drug efficacy in all these scenarios,” Kayal said. “Given these reassuring data, there should be no hesitation to prescribe biosimilars or interchangeables. Biosimilars should be positioned similarly to the reference product.”
While the efficacy of interchangeable biosimilars should come without concern, the notion of switching without the knowledge of the physician or the patient remains a mental stumbling block for many. These concerns bleed into concerns about cost.
‘Determined by the Payer’
Miguel Regueiro
A big worry for many gastroenterologists is that industry-sponsored patient assistance programs typically available for reference biologics may no longer be available for biosimilars, including interchangeables, according to Regueiro. “Thus, the out-of-pocket cost for patients may actually increase when switching from the reference biologic to the biosimilar or interchangeable,” he said.
If patients do experience cost savings when they have been switched at the pharmacy level, the result may be improved adherence, disease management and reduced risk for disease-related complications, according to Axelrad. But, at the moment, there are no guarantees of any of these outcomes.
What is certain, Regueiro noted, is that biosimilars are easier to make than biologics. “Cost savings begin with less expense in development compared with reference biologics,” he said.
Axelrad sees familiarity with various biosimilar products as beside the point. “While comfort in prescribing interchangeable biosimilars is increasing, most choice in selecting a biosimilar is really determined by the payer,” he said, “although biosimilar manufacturers are starting to implement similar support programs as those offered by bio-originator manufacturers.”
Acceptance of the role payers play in medication choice may be useful for the peace of mind of practicing clinicians, according to Regueiro. “For a physician or their office to appeal this with the payer often leads to long delays that could result in delay in treatment,” he said. “For this reason, many GIs are comfortable with nonmedical switching and have accepted this as part of their daily practice.”
The only dilemma, Regueiro noted, is that what is actually given to the patient occurs at the level of the pharmacy and not the patient or the physician. “While this should not present a problem given what I have just said, technically, the patient and prescriber may not know exactly what the patient received,” he said.
If there is a concern for Hanauer about pharmacy-level selection, it pertains to health disparities observed across the U.S. “While gastroenterologists are increasingly informed about biosimilars and interchangeables, the reach of these products varies based on region, health system and practice,” he said.
To take it a step further, in the future, when there are multiple interchangeable biologics in the same class, it is possible that each time a patient gets a biosimilar it could be a different biosimilar of the same reference biologic, Regueiro added. “Thus far, there do not appear to be issues with efficacy or immunogenicity with multiple switches, but we do not know if immunogenicity will be an issue over time,” he said.
While the FDA is heavily involved in the approval and status of interchangeable biosimilars prior to launch, the real world is a slightly different story, according to Yim. “It is difficult to sort out issues of uptake and availability, since a number of products were not immediately available in the market after FDA approval,” she said. “Biosimilar options for gastroenterology uses were limited to infliximab for a number of years and this is an intravenous infusion product.”
That said, Yim believes that success and uptake of biosimilars in fields like immunology is likely to be replicated in gastroenterology. “Accordingly, we plan to increase education efforts in the next year to include offerings tailored for gastroenterology,” she said.
Education could be critical in minimizing potential adverse consequences of biosimilar switching, including the nocebo effect.
‘Nervous About Making a Switch’
“Some patients are understandably nervous about making a switch,” Kayal said. “Their disease likely had a significant impact on their quality of life and their remission is hard-earned. They rightfully are nervous to switch course and threaten that remission.”
Education and reassurance are “key” in these situations, she added. “You should carefully explain what a biosimilar is and its equivalent safety and efficacy, and noting that the overall treatment plan and disease activity monitoring strategy do not change with a biosimilar is important.”
For Hudesman, the source of the education is as important as the information itself. “The fact that a biosimilar is interchangeable should hopefully make patients feel more comfortable about biosimilars,” he said. “However, there is still hesitancy from patients about biosimilars. The messaging and information should come from the patient’s doctor’s office, not the pharmacy or the insurance company. In my experience, if a patient first finds out about switching from a pharmacy or insurance company, they are less likely to be on board and may have a nocebo effect.”
Despite these reassurances, nocebo effects do occur. “A nocebo effect is an unfavorable therapeutic effect after a nonmedical switch from reference product to biosimilar,” Kayal said. “For example, disease activity worsening even in the absence of objective disease activity. This can be quite debilitating for patients and may prompt return to the reference product or even biologic discontinuation.”
In some cases, this effect is actually “cognitive dissonance,” according to Hanauer. “Patients perceive benefits from more expensive therapies,” he said.
There have been many reports noting that the nocebo effect may contribute to challenges in patient adoption of biosimilars and the perception of lower efficacy, according to Axelrad. “However, switching studies have confirmed the consistent efficacy of biosimilars to their originators, even in the setting of multiple, frequent switches,” he said.
To assuage concerns, Yim noted that FDA investigators conducted a systematic review and meta-analysis using statistical methods to determine whether there were safety outcome differences among individuals who switched between a biosimilar and a reference product and individuals who did not switch.
“In particular, the researchers were focused on any statistical differences in the number of deaths, nonfatal serious adverse events and study discontinuations due to an adverse event,” Yim said. “Immunogenicity events, such as the development of antidrug antibodies and neutralizing antibodies, were also examined and compared following switching.”
In the paper, which was published in PLoS One, Herndon and colleagues assessed 31 studies of patients who were switched from bio-originator products to biosimilars or from biosimilar to biosimilar. The analysis included 5,252 patients and 21 medications. Results showed overall risk differences in mortality (HR = –0.00; 95% CI, –0.00 to 0.00), serious adverse events (0.00; 95% CI, –0.01 to 0.01) and treatment discontinuation (HR = –0.00; 95% CI, –0.01 to 0.01) were essentially nonexistent.
“Immunogenicity data showed similar incidences of antidrug antibodies and neutralizing antibodies in individuals who switched and individuals who did not switch,” Yim added. “Immune-related adverse events such as anaphylaxis, hypersensitivity reactions and injections site reactions were similar in switched and non-switched people.”
Based on these data, the researchers concluded there were no differences in the risk for death, serious adverse events or treatment discontinuations between the switch and no-switch arms, according to Yim. “These results were not affected by the reference product class, the direction of the switch — meaning, reference product to biosimilar or vice versa — or the number of switches, such as a single switch vs. multiple switches,” she said. “These findings are consistent with previously published nonstatistical descriptive reviews of switching biosimilars. These findings provide additional evidence for patients and their health care providers that switching between biosimilars and their reference products is not associated with major safety events.”
In addition to these findings, Yim noted that information is available from the FDA to help clinicians talk to their patients about these products. “FDA has many resources for both patients and health care providers on our website at www.fda.gov/biosimilars under multimedia education materials,” she said.
Ultimately, interchangeable products are coming for the specialty. Regueiro believes it is important to continue to convey the message that the term “biosimilar” may, in fact, be something of a misnomer. “Although technically we have to use the term ‘similar’ — not same or equivalent — biosimilars are equivalent to biologics,” he said. “This is how I look at them based on all data. I know that there are probably still physicians and patients who are apprehensive, and the nocebo effect is probably higher. For those who are more comfortable and reassured, I think this nocebo effect is insignificant.”
Regardless of where patients fall now, Regueiro has seen improvement since the initial launch. “I can only speak to the patients I treat, but, unlike a few years ago where there was concern and apprehension over biosimilars, the patients now seem more accepting as I believe the GIs are more accepting,” he said. “The trend is moving in the right direction.”
- References:
- Herndon TM, et al. PLoS One. 2023;doi:10.1371/journal.pone.0292231.
- Ribaldone DG, et al. J Clin Med. 2021;doi:10.3390/jcm10153387.
- For more information:
- Jordan Axelrad, MD, MPH, is director of clinical and translational research at the Inflammatory Bowel Disease Center at NYU Langone Health and David P. Hudesman, MD, is co-director of NYU Langone Health’s Inflammatory Bowel Disease Center. Both can be reached at [email protected].
- Stephen B. Hanauer, MD, is Clifford Joseph Barborka Professor of Medicine at Northwestern University Feinberg School of Medicine and can be reached at [email protected].
- Maia Kayal, MD, MS, is assistant professor of gastroenterology at the Icahn School of Medicine at Mount Sinai and the Susan and Leonard Feinstein Inflammatory Bowel Disease Center and can be reached at [email protected].
- Miguel Regueiro, MD, is chief of the Digestive Disease Institute at Cleveland Clinic and can be reached at email: [email protected].
- Sarah Yim, MD, is director of the Office of Therapeutic Biologics and Biosimilars at the FDA and can be reached at [email protected].
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Sources/Disclosures
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Source:
Healio Interviews
Disclosures:
Axelrad reports receiving consultancy fees or honorarium from or being an advisory board member for AbbVie, Adiso Therapeutics, BioFire Diagnostics, Bristol Myers Squibb, Ferring, Fresenius, Janssen and Pfizer. Hanauer reports financial relationships with AbbVie, Allergan, Amgen, Arena, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cosmos, Catalys Pacific, Covance, Genentech, Gossamer, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Progenity, Prometheus, Protagonist, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, Takeda, TLL Pharma, UCB Pharma and VHsquared. Hudesman reports consulting for AbbVie and Boehringer Ingelheim. Kayal reports consulting for AbbVie, BMS, Fresenius, Janssen and Pfizer. Regueiro reports being on the advisory boards and consulting for AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Janssen, Lilly, Organon, Pfizer, Prometheus, Salix, Takeda and UCB. Yim reports no relevant financial disclosures.
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