Biosimilars were a recurring subject at the Academy of Managed Care Pharmacy (AMCP) 2024 annual meeting. On April 16, the first presentation exploring biosimilars reviewed the current landscape of these medications and their context in rheumatology, as well as showcased real-world efficacy and safety data and ongoing trends in this area.

Mark S. Box, MD, FACP, FACR, of Carondelet Rheumatology, kicked off this discussion by explaining aspects of biologic production, which are medications consisting of large, complex molecules derived from a living source.

“A slight variation may occur from batch to batch, and this has gone on since the first infliximab products came on the market,” Box explained. “And this mainly is in the side chain glycoproteins where the differences are seen . . . So even up to this point in time, patients have been exposed to slightly different medications.” With these possible variations in mind, he noted that a biologic’s approval hinges on the replication of an identical amino acid sequence from the original product. Notably, manufacturing changes of approved biologics may happen without changes to their label.

Approving biosimilars, in his words, is an “abbreviated” process that requires analytical studies, animal studies, and clinical studies. “Analyticals are the most important because if you can show that the [pharmacokinetics], the structure, are highly similar to the originator, then that's what the FDA is really looking for. In the US, it takes typically $800 million to $2 billion to develop an originator biologic over an 8- to 10-year period and taking 1000 to 2000 patients, depending on the number of indications that are going to be looked at,” he added. “A biosimilar typically costs only about $100-$200 million over 5 years and requires less than 500 patients. Usually, there's only 1 or 2 clinical trials that go on in a biosimilar product.”

Biosimilar Drug Bottle on Blue Background | image credit: Carl - stock.adobe.com

Box continued by evaluating the economic impact of biologics in the US health care system, citing that they made up an estimated 40% of total spending in 2019 despite only around 2% of patients receiving biologic prescriptions and that spending this this area increased by 160% ($100 billion-$260 billion) in the last decade.¹ Yet, the advent of small molecule generic drugs in this field contributed to approximately $1 trillion in savings between 2002-2011, and biosimilars are projected to lead to savings of $54 billion between 2017 and 2026.²

On the international scale, biosimilars such as adalimumab, etanercept, and infliximab have contributed to savings of €18 billion and are often available at prices that are 10-35% cheaper than their reference products. Furthermore, the utilizations of adalimumab, etanercept, and infliximab have increased by 22.4%, 14.5%, and 89%, respectively, as they have become more accessible and affordable to various health care systems, according to a 2023 analysis.³

There are factors that limit the uptake of biosimilars, however, such as delayed entry into the market due to patent litigation,¹overlapping patents filed for manufacturing processes and devices,⁴ and settlements with the manufacturers of a drug’s reference product before a biosimilar can be released into the market.⁵

Additionally, various deterrents have impacted the biosimilars market. Box noted strategies from reference manufacturers to maintain formulary exclusivity with payers, such as offering to give other non-generic or non-biosimilar products in a bundle if their originator biologic is either on formulary as an exclusive or, at least, still available.

Prior studies, Box added, have further revealed that over half of US physicians from specialties containing high rates of biosimilar utilization (rheumatology, gastroenterology, and dermatology) do not believe in the safety or efficacy of these medications,¹ a large majority of US physicians harbor concerns about nonmedical switching of these products,⁶ and that 40% of rheumatologists prefer prescribing to naïve patients.⁷These notions, coupled with misunderstandings about the interchangeability of biosimilars and a lack of patient awareness, have influenced lower prescription rates and created barriers for pharmaceutical substitutions.

In a real-world analysis evaluating the conversion of adalimumab in New Zealand, 40% of surveyed nurses, pharmacists and rheumatologists reported having 5 to 10 years of experience with adalimumab’s reference product.⁸ Participants reported poor satisfaction scores (5.7/10 on average) with adalimumab biosimlars, largely in areas related to training, administrative burden, drug shortages, and communication from government agencies. The difficulty of switching is another barrier to uptake, according to Box.

“That's what we're already starting to see here: a very high administrative burden at our offices trying to make these changes, explain to patients, get them back in and train them on a different product, a different injector. The nurses and pharmacists identified that the prescribers often did not discuss the switch with the patients, leading to them having more responsibility for patient education," Box said. "And that's really probably one of the worst things that you can do is just switch the patient over. They get a new thing in the in the mail from their mail or pharmacy, and it's not what they were getting before, and that's going to lead to lots of telephone calls and a lot of angst on patients.”

At present, the transition in the US has not gone well either. Box explained how savings for providers have not quite balanced the administrative burden offices are receiving. Cost differences for patients between biosimilar and reference products remain minimal, and patients have reported diminished effects from their medication after becoming aware of a biosimilar switch (known as the “nocebo effect”).⁹

Cassie Ramel, PharmD, BCPS, clinical pharmacist, Mayo Clinic, built off of Box’s discussion to explore policy-level strategies that could increase the uptake of biosimilars and overcome the aforementioned barriers.

She began by pointing to supply-side policies that have been implemented in European markets. These tactics included government interventions such as mandatory price cuts, price capping, etc., that created short-term savings; however, this approach comes with the risk of disincentivizing innovation, development, and competition between biosimilar manufacturers, which could have long-term negative impacts.³

Contrarily, there are demand-side policies that can promote the prescription of biosimilars. Ramel gave the example of an incentive program introduced in Ireland that provided a €500 gain-share for patients who either started a new biosimilar or made a switch. As a result, the utilization of etanercept and adalimumab biosimilars increased, which led to a savings of €22.7 million over 1 year.³

Aside from these strategies, Ramel also theorized on the benefits of incentivizing biosimilar development because they can take up to 9 years and $300 million to bring to market.¹⁰ Because the largest costs are clinical trials, some have proposed streamlining the approval process by assessing analytical criteria for a biosimilar that could provide financial savings and a safe medication at the same time. While Ramel said that she does not endorse a change in the FDA process, she questions the complete benefit of clinical trials in addressing, for example, rare immunogenicity concerns.

“It takes large patient populations to even see them," Ramel said. "So if we're only performing clinical trials in a few hundred patients, are we really capturing these events? Or are we kind of doing these clinical trials, having the additional costs, without giving us that additional supportive information?”

As a pharmacist, Ramel advocated for improving patient support measures to aid in transitions to biosimilars. Primarily, the importance of education cannot be understated in this process, she argued. She mentioned a 2022 survey of 900 patients with various immune-mediated inflammatory diseases that were switched to a biosimilar. In total, 1 in 5 patients reported that they had not received adequate training with their new devices, were not sure what they were injecting, and did not know how to properly inject themselves.¹¹

“And funnily enough, those patients reported worse injection pain and decreased efficacy and all those types of things. So it seems very basic . . . but having the confidence to inject yourself with this medicine, knowing how the device works, having those tools in hand and that confidence going into the injection may help overcome some of that ‘nocebo effect,’” Ramel said. In this same line of thought, Ramel emphasized the need to ensure nurses, pharmacists, and other providers are educated on these products.

Ramel then discussed the considerations behind biosimilar formulary decisions. To begin, one must ask whether the biosimilar will replace a reference product or be offered as an alternative, on the basis that it “will cover your full patient population” and be available to them across varying financial circumstances.¹² Furthermore, considerations of patients’ dose delivery and equipment are important for patient satisfaction, as well as how well the biosimilar can integrate into an existing system (electronic health records, barcoding, etc.) and the dependability and track record of a manufacturer.

Once a product has been picked, Ramel emphasized the importance of thinking through additional costs, such as those related to patient transitions if they need a new provider, education for both patient and provider, and a pharmacovigilance system should a patient need to report a problem they are experiencing. Additionally, plans should be in place to encourage the uptake of biosimilars, establish new biosimilars in the future, and prepare for and respond to the possibility that a patient will not be able to take a biosimilar.

References

1. Zhai MZ, Sarpatwari A, Kesselheim AS. Why are biosimilars not living up to their promise in the US? AMA J Ethics. 2019;21(8):E668-678. doi:10.1001/amajethics.2019.668

2. GPhA report: Savings: $1 trillion over 10 years – generic drug savings in the U.S., J Pharm Health Serv Res. 2012;3(4):229-236. doi:10.1111/jphs.12000

3. Car E, Vulto AG, Houdenhoven MV, Huys I, Simoens S. Biosimilar competition in European markets of TNF-alpha inhibitors: a comparative analysis of pricing, market share and utilization trends. Front Pharmacol. 2023;14:1151764. doi:10.3389/fphar.2023.1151764

4. Cottler M, Whitehill J, Siedor A. The 2018 biosimilar litigation landscape: A primer. Biopharma Dive. December 14, 2017. Accessed April 17, 2024. https://www.biopharmadive.com/news/the-2018-biosimilar-litigation-landscape-a-primer/512982/

5. Urquhart L. Market watch: Top drugs and companies by sales in 2017. Nat Rev Drug Discov. 2018;17(4):232. doi:10.1038/nrd.2018.42

6. Cohen H, Beydoun D, Chien D, et al. Awareness, knowledge, and perceptions of biosimilars among specialty physicians. Adv Ther. 2017;33(12):2160-2172. doi:10.1007/s12325-016-0431-5

7. Jacobs I, Singh E, Sewell KL, Al-Sabbagh A, Shane LG. Patient attitudes and understanding about biosimilars: an international cross-sectional survey. Patient Prefer Adherence. 2016;10:937-48. doi:10.2147/PPA.S104891

8. Ferreri D. Study documents HCPs’ experiences of a mandatory switch to inform future transitions. AJMC: The Center for Biosimilars. December 2, 2023. Accessed April 17, 2024. https://www.centerforbiosimilars.com/view/study-documents-hcps-experiences-of-a-mandatory-switch-to-inform-future-transitions

9. Shubow S, Sun Q, Nguyen Phan AL, et al. Prescriber perspectives on biosimilar adoption and potential role of clinical pharmacology: A workshop summary. Clin Pharmacol Ther. 2023;113(1):37-49. doi:10.1002/cpt.2765

10. Cohen HP, Turner M, McCabe D, Woollett GR. Future evolution of biosimilar development by application of current science and available evidence: The developer's perspective. BioDrugs. 2023;37(5):583-593. doi:10.1007/s40259-023-00619-0

11. Kaneko K, Prieto-Alhambra D, Jacklin C, et al. Influence of information provided prior to switching from Humira to biosimilar adalimumab on UK patients' satisfaction: a cross-sectional survey by patient organisations. BMJ Open. 2022;12(2):e050949. doi:10.1136/bmjopen-2021-050949

12. Ismail S, Abu Esba L, Khan M, Al-Abdulkarim H, Modimagh H, Yousef C. An institutional guide for formulary decisions of biosimilars. Hosp Pharm. 2023;58(1):38-48. doi:10.1177/00185787221138007