In the United States, although the first biosimilar obtained approval from the FDA in 2015, these drugs have been slow to gain support and implementation in clinical practice. Biosimilars of several anti–tumor necrosis factor (TNF) agents have been approved. Currently, 3 infliximab biosimilars are available for the treatment of inflammatory bowel disease (IBD).

Although the infliximab biosimilars are approved for the same indications as the reference infliximab, research shows that many gastroenterologists are still reluctant to use infliximab biosimilars for Crohn disease (CD) or ulcerative colitis (UC).

 Perhaps the most common reason is that insurance coverage for biosimilars has not been widely available, making it difficult to prescribe or switch them. However, even when biosimilars are covered, providers may still hesitate to use these agents. They may not know about biosimilars or their safety and efficacy, or they may lack clinical experience in using them.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful difference from an existing FDA-approved reference product.

 In order to understand biosimilars, one must understand the “totality of evidence” approach, which forms the foundation of biosimilar development programs. In the early stages of biosimilar development, extensive, rigorous studies are conducted to demonstrate structural and functional similarity between the reference biologic and biosimilar. Once this similarity is established, clinical studies are conducted in one or more sensitive populations to “confirm” equivalent efficacy and safety.

 Biosimilars undergo a thorough regulatory review process, and biosimilars approved by the FDA can be regarded as safe and effective for use based on robust scientific evidence.

Are Biosimilars Safe for Patients With IBD?

Biosimilars were introduced earlier in Europe than in the United States, and they have been used without major safety issues for more than 10 years. Several real-world studies conducted in Europe demonstrate the safety of switching from reference infliximab to biosimilars, or from one biosimilar to another biosimilar in the IBD population. One long-term observational, prospective cohort study conducted in Germany showed that switching 148 patients with IBD (96 with CD, 52 with UC) from reference infliximab to a biosimilar did not lead to any increase in disease activity.

 In another prospective, single-center observational study conducted with 221 patients (179 with CD, 42 with UC), there was no adverse effect on IBD control or drug levels after the first or second switch.

In the United States, real-world evidence on biosimilars for patients with IBD has been rather limited, but the data are growing with increasing use of biosimilars. Recently, at the American College of Gastroenterology (ACG) 2020 Virtual Annual Scientific Meeting, held from October 26 to 28, 2020, real-world data on US veteran patients with IBD revealed that a single switch from reference to biosimilar infliximab, or a double switch from the reference product to a biosimilar to another biosimilar, did not lead to any significant safety issues.

 Patients who were stable on the original infliximab medication for at least 3 months were eligible for the study, and they continued to remain stable after switching.

In another real-world study conducted by Cleveland Clinic, patients were randomized to switch to infliximab biosimilar or continue on reference infliximab. The study demonstrated that there was no significant difference in the use of corticosteroid taper, maintenance of remission rates, fecal calprotectin levels, infliximab concentrations, or antibody levels between these 2 groups.

 Since data are limited on multiple switching of biosimilars to reference product or from one biosimilar to another, this information would be important for the FDA to authorize interchangeable status for a biosimilar, which would allow pharmacists to independently substitute biosimilars when dispensing. No biosimilars have that designation to date.

How Does COVID-19 Affect the Use of Biosimilars?

Use of biosimilars can help drive down overall health care costs. Especially now, as the United States continues to battle the coronavirus disease 2019 (COVID-19) pandemic, there will be an increasing burden on the health care system to finance budgets and find savings to ease some of that burden for patients, providers, payers, and employers. Development of new vaccines and treatments for COVID-19 requires billions of dollars of funding from both private and public sources. And trillions of dollars are needed to support hospitals and health care providers for costs and expenses associated with COVID-19. This is an enormous strain on the health care budget, but there is room to drive down the cost of existing medicines through wider adoption of biosimilars.

Also, as patents expire on some biologic molecules in the next few years, there will be more biosimilars available for a wider spectrum of therapies in the market. For adalimumab, 6 biosimilars have FDA approval to enter the US market in 2023 and more are anticipated.

 Will rheumatologists, gastroenterologists, and dermatologists in the United States be ready to use biosimilars by then?

It will be interesting to see how biosimilars change the daily practice of IBD treatment in the coming years. With approximately 3 million Americans living with IBD, and the burden and prevalence of IBD continuing to increase,

 it’s time to embrace the change and think with a holistic point of view. Biosimilars, as treatment options with lower cost than reference products but with the same efficacy and safety, can be the optimal solution to maintain quality care for patients while reducing the cost burden on the health care system in the United States.

1. Park SH, Park JC, Lukas M, Kolar M, Loftus EV. Biosimilars: concept, current status, and future perspectives in inflammatory bowel diseases. 

. 2020;18(1):34-44. doi:10.5217/ir.2019.09147

2. FDA. Biosimilar and interchangeable products. Updated October 23, 2017. Accessed October 2020. 

https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products

3. FDA. Biosimilar development, review, and approval. Updated October 20, 2017. Accessed October 2020. 

https://www.fda.gov/drugs/biosimilars/biosimilar-development-review-and-approval

4. Fischer S, Mesfin S, Klenske E, et al. P548 Efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar SB2 in inflammatory bowel disease patients: A long-term observational, prospective cohort study. 

2020;14(Suppl 1):S466-S467. doi:10.1093/ecco-jcc/jjz203.676

5. Luber R, O’Neill R, Singh S, Arkir Z, Irving P. P485 Switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with the first or second switch. 

6. Pernes T, Patel M, Khan N. The safety of switching from originator infliximab or CT-P13 to SB2 among a nationwide cohort of inflammatory bowel disease patients. Presented at: ACG 2020 Virtual; October 23-28, 2020. Poster 1597.

7. Padival R, Heis F, Lee JA, et al. Real world comparison of originator infliximab versus the biosimilar infliximab-abda in the treatment of inflammatory bowel disease. Presented at: ACG 2020 Virtual; October 23-28, 2020. Poster 1625.

8. Davio K. FDA approves Pfizer’s adalimumab biosimilar, Abrilada. The Center for Biosimilars

. Published November 16, 2019. Accessed October 2020. 

https://www.centerforbiosimilars.com/view/fda-approves-pfizers-adalimumab-biosimilar-abrilada

9. Centers for Disease Control and Prevention. Inflammatory Bowel Disease Data and Statistics. Updated August 11, 2020. Accessed October 2020. 

https://www.cdc.gov/ibd/data-statistics.htm

Bincy P. Abraham, MD, explains that even when payers allow coverage for biosimilars, providers may still be hesitant to use them. 

Opinion: Embrace the Era of Next-Generation Biologics

Bincy P. Abraham, MD, MS, AGAF, FACG, is a professor of Clinical Medicine at Houston Methodist Academic Institute. She is also the distinguished professor and director of the Fondren Inflammatory Bowel Disease Program at the Underwood Center for Digestive Disorders and director of Gastroenterology Fellowship Program at Houston Methodist Hospital.

Bincy P. Abraham, MD

Corey Greenblatt, MPH, is the manager of policy and advocacy of CreakyJoints and The Global Healthy Living Foundation. The Global Healthy Living Foundation is a 501(c)(3) non-profit organization whose mission is to improve the quality of life for people living with chronic illnesses (such as arthritis, osteoporosis, migraine, diabetes, psoriasis, and cardiovascular disease) by advocating for improved access to health care at the community, state, and federal levels, and amplifying education and awareness efforts within its social media framework. The Global Healthy Living Foundation is the parent organization of CreakyJoints, the digital community and advocacy organization for millions of arthritis patients and caregivers worldwide who seek education, support, advocacy, and patient-centered research through ArthritisPower, the first-ever patient-centered research registry for joint, bone, and inflammatory skin conditions. Visit 

Corey Greenblatt, MPH

Last week the US Food and Drug Administration (FDA) issued a revised draft guidance detailing its policies on mixing, diluting, and repackaging certain types of biological products outside of the scope of an approved biologics license application (BLA).

Diluting or mixing a biological product with other components, or repackaging a biological product by removing it from its approved container-closure system and transferring it to another container-closure system, in the absence of manufacturing controls, is highly likely to affect the safety and/or effectiveness of the biological product. The FDA says even minor manipulations of biologics can result in quality or safety issues due to their unique properties.

There are instances where appropriate to mix or dilute a biological product to meet the needs of specific patients. "For example, for some biological products there is no licensed pediatric strength and/or dosage form, so the product is diluted for use in pediatric patients." While there are exemptions from certain federal regulations for compounded drugs under sections 503A and 503B of the 

, these exemptions do not apply to biological products licensed under sections 351(a) or (k) of the 

In accordance, the FDA says that any biological product that is mixed, diluted, or repackaged outside the scope of an approved BLA is an "unlicensed biological product." It also does not intend to take actions for violations of section 351 of the PHS Act or sections 502(f)(1) or 582 of the FD&C Act if a state-licensed pharmacy, a federal facility, or an outsourcing facility mixes, dilutes, or repackages a biological product" in accordance with the guidance.

The guidance does not apply to investigational new drugs being studied under a new drug application or radioactive biological products.

Biologics Mixing, Diluting, and Repackaging: FDA Draft Guidance

Daniella (Dee) Latham

David T. Rubin, MD, AGAF, is a professor of medicine and section chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine. He is a fellow of the American Gastroenterological Association (AGA), which represents over 16,000 gastroenterologists worldwide and is dedicated to empowering clinicians and researchers to improve digestive health. He is also chair-elect of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, whose mission is to cure Crohn disease and ulcerative colitis, and to improve the quality of life of children and adults affected by these diseases. AGA is a member of the Biologics Prescribers Collaborative (BPC), an organization comprising medical societies whose members regularly prescribe biologic medicines. BPC strives to ensure that sound policies are in place to promote the safest possible development and use of all biologics, including biosimilars, for all patients.

David T. Rubin, MD, AGAF

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John Bujnoski is Managing Director of Pangea Advisory and Consulting, LLC, a strategic marketing consulting firm focused on the specialty biopharmaceutical and biosimilar market segments. John has extensive global biopharmaceutical industry expertise including extensive knowledge and understanding of the global market environment including pricing, market access, and reimbursement systems.

John Bujnoski

Safaraz Niazi, PhD, is an adjunct professor of biopharmaceutical Sciences at the College of Pharmacy at the University of Illinois at Chicago. 

Sarfarzaz K. Niazi

George C. Yu, JD, is a partner in the Intellectual Property group of Schiff Hardin LLP. He is an experienced patent attorney who focuses his practice focuses on patent infringement litigation and counseling and has worked in private practice and in-house positions. George has litigated patents relating to recombinant proteins, monoclonal antibodies, microarray technology, and small molecule therapeutics. George has advised companies developing novel biologics as well as biosimilars on patent strategy.

George C. Yu, JD

Coronavirus disease 2019 (COVID-19) altered the workflow in all areas of the health care and life sciences industries. The FDA was not exempt from pandemic-induced upheaval. Meetings of advisory committees, which provide the FDA with expert advice on scientific, technical, and policy matters, were often postponed, and although drugs were still reviewed and approved, significant delays occurred.

From the start of the United States’ response to the COVID-19 pandemic in March 2020 until late summer, 2 biosimilars were 

: Hulio (adalimumab) and Nyvepria (pegfilgrastim). This represented not only an improvement in patient access and affordability of life-changing medications, but also a slowdown in biosimilar approvals.

In previous years, biosimilar approvals had steadily increased. As shown in the figure, the projected trend suggested approximately 12 biosimilar approvals for 2020 and 14 for 2021.

The trend line for biosimilar approvals suggested 2020 would be another strong year for the emergence of these lower-cost therapies; however, just 2 had been approved by the midyear point.

Although other factors came into play, such as patent expirations and product development, it appeared unlikely that the total of 12 biosimilar approvals would be achieved in the final quarter of 2020, and there was even potential for this slower pace to extend into 2021.

There were other reasons why patient access did not improve as expected. Typically, once manufacturers receive biosimilar approval, many face 

 that delay products from reaching the market promptly. These court cases often are purposely filed to interfere with market access to a new product. In some cases, “

” agreements postpone market entry of a biosimilar for many 

The COVID-19 crisis extended these delays because court systems temporarily closed to prevent spread of the virus and reopenings were late or occurred only in stages. Well into 2020, virus hot spots 

 to stall judiciary system operations, adding to the time needed to achieve market access for these new therapy options.

In addition to regulatory and judicial barriers, the overwhelming workflow within health systems also played a role in limiting access to new therapies. When health care facilities are in crisis mode, many components of the reimbursement and education processes, each of which is vital for biosimilar uptake, are hindered. 

Pharmacy and therapeutics (P&T) committees are necessary for ensuring new therapies will be included in the health care facility formulary. From the start of COVID-19, P&T meetings were often conducted virtually or 

 on evaluating emerging therapies for COVID-19 treatment, leaving little time for consideration of other formulary additions. With so much focus on COVID-19, little time was allocated to much else.

Within hospitals, the same was true regarding in-service education for physicians. With a need to educate physicians on current protocol, diagnostics, and treatment surrounding COVID-19, there was not much time left to educate on biosimilar therapies and novel agents.

“Lunch and learn” programs were likely on hiatus during the pandemic due to social distancing requirements, understaffing, and a strain on funding. Gathering professionals into a conference room could not be prioritized over keeping everyone safe.

Typically, many facilities partner with manufacturers to supply marketing materials and food to lunch and learns, and a clinical staff member presents on the topic at hand. As manufacturer field teams were grounded, less information reached the health care providers. Most nonessential visits were prohibited to prevent unnecessary risk of virus spread. These grounded professionals included sales representatives who provide information about new products, field reimbursement specialists who assist in getting products approved by the health plans, and medical science liaisons who can discuss new products on a higher level. These professionals were not as physically active as the pandemic unfolded and virtual methods of interaction were implemented.

If new therapies, including biosimilars, were not approved by the FDA, litigated promptly in the courts, cleared for formulary placement, or explained to physicians, it is unlikely patients were learning much about them. Especially when it comes to biosimilars, patients need to be aware of their potential options and the associated benefit of cost savings. With COVID-19, the nation entered a time of financial instability and loss of health care coverage, and these new therapy options became even more important for safe and affordable health care.

Coronavirus disease 2019 altered the workflow in all areas of the health care and life sciences industries, and the FDA was not exempt from pandemic-induced upheaval.

The Pandemic's Multilevel Effect on Patient Access

Amanda DeMarzo, PharmD, MBA, PACS, is the associate director of Patient Access with the National Board of Prior Authorization Specialists, an affiliate of the Accreditation Council for Medical Affairs, based in Oradell, New Jersey. She focuses on how to improve the current health care system as a whole through improved training, widespread certification, and advanced technology for better patient outcomes. She developed a passion for patient-centered care and shared decision making during patient-facing roles over the last 8 years.

Amanda DeMarzo, PharmD, MBA, PACS

The House of Representatives has approved the bipartisan 21st Century Cures legislation, which includes funding for innovative research and provisions to speed up the drug approval process.

By a vote of 392-26, the House approved the 21st Century Cures Act. The House had passed an earlier version of the bill in July 2015 but continued to revise and update it, releasing the most recent draft of the bill last week. These updates included provisions for mental health, substance abuse, and child and family services.

Members of both political parties have been vocal in their support of the legislation, often citing its passage as a top priority during the lame-duck Congressional session. Prior to the election, Senate Majority Leader Mitch McConnell, R-Kentucky, had said it “could end up being the most significant piece of legislation we pass in the whole Congress." 

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