The ‘great American switching experiment’: Cyltezo debut ushers in interchangeable era
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The hotly debated topic of interchangeability between biologics and biosimilars has officially leapt from the hypothetical realm to clinical practice, ushering in a new era of therapy switching in rheumatology.
Cyltezo (adalimumab-adbm, Boehringer Ingelheim), the first biosimilar indicated for certain inflammatory diseases to achieve the interchangeable designation from the FDA, made its U.S. debut on July 1. This means that it is now possible for a patient being treated with adalimumab (Humira, AbbVie)to be switched to Cyltezo without additional approval from the prescriber.
Source: Madelaine A. Feldman, MD, FACR
According to the FDA, this may occur at the pharmacy subject to state pharmacy laws, which vary across the country, a practice commonly called “pharmacy-level substitution” — similar to how generic drugs are substituted for brand-name drugs.
Madelaine A. Feldman, MD, FACR, vice president of advocacy and government affairs at the Coalition of State Rheumatology Organizations, and founder and past president of the Rheumatology Alliance of Louisiana, described the situation in another way — “The great American switching experiment.” And it has already begun.
“Health insurance companies have been switching patients back and forth on non-interchangeable biosimilars for several years now,” Feldman told Healio Rheumatology. “I used that that phrase — ‘the great American switching experiment’ — when I testified before the Arthritis Advisory Committee of the FDA during the approval of the first adalimumab biosimilar, to describe how health insurance companies would start switching patients back and forth or various biosimilars depending on which on made them the most money, regardless of interchangeability designation.”
Feldman noted that, at that time, there was ongoing talk of “switching studies” that would be required for a biosimilar to obtain an interchangeable designation.
“I knew back then that ‘switching studies’ wouldn’t matter to pharmacy benefit managers because they already had no qualms about switching patients to completely different medicines, for profit reasons,” she said. “Because the formulary dictates what will be paid for — and even biosimilars are expensive — pharmacists’ substitution of a biosimilar becomes moot if the drug isn’t fully covered on the formulary.”
Robert W. Levin, MD, past president of the Florida Society of Rheumatology, president of the Alliance for Transparent and Affordable Prescriptions, and associate affiliate professor of medicine at the University of South Florida, expressed what has become a relatively common refrain among rheumatologists regarding this development.
“I knew this was coming and I am not comfortable with the concept,” he said.
The concerns expressed by Levin are both patient-centered and financial.
“Patients are going to go to the pharmacy to get an injectable, and suddenly they are presented with a different device or syringe,” he said. “This can lead to the nocebo effect. It will take some getting used to for them.”
This is not to mention changes in cost and other financial implications at both the patient and systemic levels.
However, John R.P. Tesser, MD, adjunct assistant professor in the division of clinical education at Midwestern University, Arizona College of Osteopathic Medicine, and partner in Arizona Arthritis & Rheumatology Associates, represents another school of thought in the rheumatology community.
“My thoughts on interchangeability have been evolving over the last 7 or 8 years,” he said.
Like many practitioners, Tesser was initially uncomfortable with the concept when it was first introduced.
“But I have been moving toward a different vantage point, recently, based on our experience with infliximab biosimilars,” he said. “Recently, we have been able to choose one or another and have had experience with patients going back and forth with the reference biologic, and in most cases it does not appear to make a difference — with some nocebo exceptions. Why would it be different with adalimumab?”
No matter which side of the debate one falls on, the fact is that the era of non-medical switching to interchangeable biosimilars is here. Understanding the issues at hand could help rheumatologists manage it as safely and effectively as possible.
‘Can’t Be Better, Can’t Be Worse’
Although many rheumatologists are familiar with the concept of interchangeability, understanding the FDA definitions at hand may be useful in communicating to patients exactly what is happening. The most important difference pertains to the distinction between biosimilarity and interchangeability.
Unlike a reference product, which is approved in a standalone application, all biosimilars and interchangeable biosimilars are approved through a shortened process that compares the new product to the reference drug to show biosimilarity, according to the FDA. However, for interchangeable biosimilars, manufacturers must provide additional data regarding how the interchangeable product may be used in the marketplace with patients. The aim of these studies is to assess whether switching is safe.
“Manufacturers generally conduct studies in which patients alternate between the reference product and the interchangeable biosimilar and compare those patients to patients who are just being treated with the reference product,” said the FDA in an explainer on interchangeable biological products available on its website. “The results must show no decrease in effectiveness or increase in safety risk associated with switching.”
This process was followed by Boehringer Ingelheim in the development of Cyltezo, which was first approved as a biosimilar in 2017 and later granted the interchangeable designation in 2021.
In the phase 3, randomized VOLTAIRE-X clinical trial, Cyltezo sufficiently demonstrated equivalent pharmacokinetics, efficacy, immunogenicity and safety as Humira between the switching and continuous treatment groups. The results of the trial were presented at the American Academy of Dermatology 2021 conference.
“All biosimilars have to prove is similar pharmacokinetics and similar clinical results in one disease to get approved, and that approval gets generalized into multiple indications,” Levin said.
For example, if a prospective adalimumab biosimilar is approved for psoriatic arthritis, it can then be applied to ankylosing spondylitis, psoriasis, rheumatoid arthritis or other conditions, he said.
“Chemically and structurally, there can be differences between a biosimilar product and the bio-originator, as long as the clinical performance is the same,” Levin said.
He additionally highlighted another important concept of interchangeability.
“It turns out that if the biosimilar has better clinical results than the originator, it does not pass,” he said. “It has to be similar. It can’t be better, it can’t be worse.”
Theoretically, if a patient is switched from one medication to another that is “not better” and “not worse,” the outcome should be the same. However, this is not always the case. Some experts find this problematic.
‘If It Ain’t Broke, Don’t Fix It’
The FDA has been careful to draw distinctions about what interchangeability means in the context of a bio-originator with multiple biosimilars. For example, the administration has stated that an interchangeable biosimilar is not necessarily safer or more effective than other biosimilars.
However, for some experts, whether the biosimilar is simply similar or interchangeable is beside the point. A more relevant concern is how changing medications can impact the patient’s experience overall.
In a paper published in Current Medical Research & Opinion, Nguyen and colleagues examined non-medical switching across a variety of economic and patient behavioral parameters in 29 studies conducted between 2000 and 2015. Results showed that more than 60% of studies demonstrated clinical implications of the switch, while 4.2% impacted medication-taking behaviors.
Importantly, 33.3% of associations with non-medical switching were negative, while 55.2% were neutral and just 11.5% were positive. Moreover, in patients with stable or well-controlled disease, nearly 70% of patients reported negative associations with non-medical switching.
“The patient may react differently to the new medication, causing new side effects,” Allan Gibofsky, MD, JD, professor of medicine and public health at Weill Medical College of Cornell University, and attending rheumatologist at the Hospital for Special Surgery, in New York, said in an interview. “Also, the new medication may be of a new class of agents and may not be as effective at treating the underlying condition, causing a reemergence of the previous symptoms.”
Even when switching from one biologic to another, there can be differences in adverse events and efficacy, according to Gibofsky.
“With respect to biologics, one biologic may be more immunogenic than another, which can result in an allergic reaction,” he said. “Non-medical switching has also been shown to increase the chance of a second medically necessary switch in medication in the 2 years following the switch.”
The reason is that non-medical switching can “reduce the overall health experienced by many patients,” according to Gibofsky.
“As a result, patients who have been switched for non-medical reasons often utilize more medical services than stable patients who are not switched,” he added. “This results in an increase in overall medical costs per patient to be met by the insurer.”
Before discussing the financial implications of non-medical switching, it is important to consider the effect it will have on clinicians.
“Rheumatologists like to know that patients are receiving what is being prescribed — whether it is a biologic or a small molecule,” Gibofsky said. “The decision of what to prescribe is a complicated and individualized one and involves shared decision making with the patient as well.”
This is particularly true for stable patients, he added.
“The rule is: If it ain’t broke, don’t fix it,” Gibofsky said.
There is also the looming issue of the nocebo effect, which lies at the heart of many of the fears surrounding non-medical switching.
‘Whittling Away at the Trust’
The nocebo effect is, essentially, the worsening of symptoms triggered by a patient’s negative feelings regarding an intervention, therapy or sham. This effect can be experienced when a patient anticipates a negative impact associated with a drug or therapy — or a change in drug or therapy.
“Substituting a biosimilar for a reference product without notifying the rheumatologist is fraught with danger for a number of reasons, including the nocebo effect,” Feldman said.
The first issue is that patients may be “confused” or “frightened” that they are being treated with the incorrect medication, according to Feldman.
“This sets the nocebo reaction in motion,” she said.
Tesser explained this from the patient perspective.
“One problem is that the switch is happening at the pharmacy, without the prescribing physician ordering, knowing or being informed of the switch necessarily, depending on the state’s pharmacy rules,” he said. “When we give many intravenous drugs, the patient does not know what color the package is, they do not know what the box looks like, and they just receive it. But when they get Humira versus another adalimumab biosimilar, there is a different box, a different device. If they are not prompted that this is going to happen, I am afraid this is going to cause significant anxiety and concern.”
However, even when the patient has received sufficient notice ahead of time, the nocebo effect can still occur, according to Tesser. There are data to support this assertion, as well.
In a paper published in the European Journal of Clinical Pharmacology, Boone and colleagues conducted a 1-year investigation of infliximab (Remicade, Janssen) switching in 146 patients with inflammatory bowel disease, RA, PsA and AS. Results demonstrated an overall nocebo response rate of 12.8% through 6 months of follow-up.
“This can result in our patients feeling uncomfortable with the ‘new’ drug that was sent to them before we even had a chance to discuss the change, which certainly can lead to a nocebo effect,” Feldman said.
However, the issue for Feldman goes beyond concern that the drug will not work.
“The patient potentially can lose trust and confidence in their rheumatologist, worsening the nocebo effect not only for that drug, but also perhaps whittling away at the trust in the entire relationship,” she said.
In a paper published in BioDrugs, Kristensen and colleagues aimed to offer solutions for mitigating or minimizing the nocebo effect in the setting of biologics and biosimilars.
“We propose three key strategies to help mitigate the nocebo effect in clinical practice when switching patients from reference biologic to biosimilar,” they wrote.
According to the authors, these strategies are positive framing, improved understanding of biosimilars among patients and health care professionals alike, and the use of a managed switching program.
In addition to these strategies, Tesser recommended ongoing communication with every patient as interchangeable switching becomes more common.
“The level of sophistication and understanding will vary from patient to patient,” he said. “It is important to answer all of their questions, about how the medications will work, about what will happen at the pharmacy or their infusion center, about the manufacturer, and, of course, about how the medication will impact them.”
Tesser stressed that these discussions should include explicit statements that the medicine is essentially — though not exactly — the same.
“It is just manufactured by a different company,” he said.
As rheumatologists continue to grapple with the clinical implications, assessing the financial concerns may also be beneficial to minimize obstacles as rheumatology gains more interchangeable drugs.
‘Fait Accompli’
According to the FDA, there is an important non-medical rationale for shepherding more interchangeable and biosimilar drugs through the approval process — their potential to lower drug costs.
“Interchangeable biological products (also called interchangeable biosimilars or interchangeable products) may help increase patient access to biologics,” stated the FDA in its explainer on interchangeable therapies.
Although Gibofsky is hopeful that more approved medications will lead to increased access for patients, he expressed concerns about whether this will actually come to pass.
“The rationale for these bio-originator to biosimilar substitutions or switches is purely economic, as it is assumed that it costs the insurer less to purchase and dispense the biosimilar than the bio-originator,” he said.
However, additional data from the Nguyen study showed that around one-fifth of non-medical switching instances resulted in outcomes that impacted resource use, while almost 15% had economic impacts.
“Non-medical switching is usually driven by insurance companies who aim to switch stable patients to less expensive medications, in the hope of lowering costs,” Gibofsky said. “While Non-medical switching is undoubtedly a cost-motivated move from the insurance company, research suggests that it may not be an effective strategy for reducing costs.”
For Levin, the issue is more a matter of personal finances for patients.
“AbbVie has a really great patient support program, which includes rebates, patient assistance or nurse ambassador programs, and help with out-of-pocket costs,” he said. “It is unclear whether the biosimilar manufacturers who enter the market will offer similar benefits. We also do not know the impact on cost from the specialty pharmacies or pharmacy benefit managers.”
Another concern is the nebulous nature of drug pricing in general.
For example, the Humira biosimilar Amjevita (adalimumab-atto, Amgen) has two different price schedules, according to Levin.
“One is 50% off Humira and one is slightly below Humira,” he said. “But who knows when one is used rather than the other.”
That said, Levin does believe that, in the long run, drug prices could fall with the advent of more biosimilars in the market, non-medical switching notwithstanding. In one potential bright spot, Coherus BioSciences announced in June that its Humira biosimilar Yusimry (adalimumab-aqvh) will make its debut in the U.S. marketplace this summer at an 85% discount compared with the originator.
“I anticipate that list prices could come down with more competition,” he said. “Then again, pharmacy benefit managers tend to prefer higher-priced medications, so it is difficult to say how much of this will reach the patient.”
According to Feldman, pharmacy benefit managers will figure out a way to switch, but only to the drugs that “make them the most money.”
“That is what they call the ‘lowest net cost,’” she added. “Biosimilars are supposed to bring down the price, but will that price be low enough to afford if it is not covered by insurance?”
However, one “silver lining” could be seen among self-insured employers who pay for the care of their employees, Feldman noted.
“For example, employers paying $800 per month for a drug without rebates is a much better deal than $4,000 per month after rebates,” she said. “Who needs rebates if the price is low enough?
“Up until now, the two things that gave a drug the best chance of being preferred on a formulary were higher price — to give a bigger legal kickback — and market share,” she added. “At the moment, biosimilars have neither. Let’s hope that if lowest price biosimilars — interchangeable or not — gain a foothold in the self-insured market, this could turn that entire model around.”
Regarding nonmedical switching, either of one agent in a class for another, or even of a bio-originator to a biosimilar, Gibofsky additionally noted that the cost savings to the insurer may not result in any savings — of time or effort — to the physician.
“There is usually no reduction in the effort for prior authorization and thus no meaningful tangible benefit to the physician to participate in payer non-medical switching programs,” he said.
Tesser, meanwhile, used the issue of administrative burden to argue that it may actually be preferential that prescribers go without notification in cases of interchangeable switching at the pharmacy — at least in those cases where they truly do not have a say in the matter.
“We are moving toward an environment where patients will go from one biologic to a biosimilar, and back, without our knowledge,” he said. “If we need to be told every time this happens, I’m concerned we are going to be inundated with a ton of faxes providing us updates at each step of the transition. Do we really want to see that when we are unable to do anything about it? It will only add to our administrative burden.”
Tesser additionally pointed to history for evidence that the current concerns and stresses regarding non-medical switching of biologics and interchangeable biosimilars may ultimately become a thing of the past.
“When the Waxman-Hatch Act was passed in 1984, there was a huge outcry about allowing generic medications to come onto the market,” he said.
The implication is that most physicians have ceased to worry about whether a patient is receiving a name-brand or generic medication for small molecule drugs, and that the same pattern is likely to play out in the biologic space. Although Tesser acknowledged that the difference between a bio-originator and a biosimilar is not the same as the distinction between a small molecule and its generic version, he noted that rheumatologists have long managed the variability in biologic medications.
“The Remicade that was made in 1999 is not the same as it is now,” he said. “Manufacturing techniques change, cell cultures change, the biologic molecule is not exactly the same. Perhaps this could be one reason why a patient who has been taking Remicade or Enbrel (etanercept, Amgen) for 10 years suddenly stops responding.”
The point is that switching a patient from one biologic or biosimilar to another — even when both doctor and patient have agreed upon the switch — can come with clinical pitfalls.
It is for this reason, among others, that despite his reservations, Levin has also taken a similarly sanguine approach.
“Non-medical switching is a fait accompli,” he said. “How I feel about it does not necessarily change anything. It is just going to take some getting used to.”
- References:
- Boone NW, et al. Eur J Clin Pharmacol. 2018;doi:10.1007/s00228-018-2418-4.
- Kristensen LE, et al. BioDrugs. 2018;doi:10.1007/s40259-018-0306-1.
- Nguyen E, et al. Curr Med Res Opin. 2016;doi:10.1185/03007995.2016.1170673.
- FDA on Interchangeable products: www.fda.gov/media/151094/download#:~:text=An%20interchangeable%20biological%20product%20is,depending%20on%20state%20pharmacy%20laws.
- FDA on prescribing: www.fda.gov/files/drugs/published/Prescribing-Interchangeable-Products.pdf.
- For more information:
- Madelaine A. Feldman, MD, FACR, can be reached at 2633 Napoleon Ave. Suite 530 New Orleans, LA 70115; email: madelainefeldman@gmail.com.
- Allan Gibofsky, MD, JD, can be reached at 535 E. 70th St, New York, NY 10021; email: gibofskya@hss.edu.
- Robert W. Levin, MD, can be reached at 1831 North Belcher Road, Clearwater, FL 33765; email: daniel.rene@kglobal.com.
- John R.P. Tesser, MD, can be reached at 5601 W Eugie Ave, Glendale, AZ 85304; email: jtesser1@cox.net.
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