Tony Hagen is senior managing editor for The Center for Biosimilars

Highlighting challenges and ongoing efforts, Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars (OTBB) delivered a progress report on the FDA’s Biosimilars Action Plan (BAP) at the Association for Accessible Medicine (AAM) GRx+Biosims annual conference.

The BAP was created in 2018 to support biosimilar development by improving efficiency of the development and approval process; improving scientific and regulatory guidance; improving education about biosimilars for patients, clinicians, and payers; and improving the competitive environment by “reducing gaming of FDA requirements or other attempts to unfairly delay competition,” Yim said.

The FDA continues work to develop indices of critical quality attributes for biosimilars, identify pharmacodynamic (PD) biomarkers, and investigate in silico modeling, in which computers are used to model pharmacologic or physiologic processes. Each of these qualifies as a potential development tool, “but because of resource limitations related to [coronavirus disease 2019], we are not yet ready to release the first batch of biosimilar product recommendations. Hopefully, we’re close,” Yim said.

 to help biologics developers and other stakeholders to understand at what point the exclusivity protection clock begins to tick for a reference product. The guidance was also intended to help innovator companies know what information to provide the FDA to help the agency decide when product exclusivity begins. Six years later, that guidance is still in draft form, although progress continues, Yim said. “We’re still working on biologic product regulatory modernization and finalizing guidance on reference product exclusivity and post-approval manufacturing.”​ 

The FDA would like to make various improvements to improve biosimilar development, and these include optimizing review staff time, exploring PD markers and assays that can help ascertain biosimilarity between biosimilar candidates and reference products, providing product specific guidance, and partnering with international regulatory authorities to reduce redundant activities. “To take product development and review to the next level in efficiency, more will need to be done,” Yim said.

“We’ll need to improve the status of biosimilar-related knowledge management and expand its scope to ensure not only consistency but provide space for ideas regarding improvements in best practices to be easily known and shared,” she said.

Another area of focus that could lead to important gains for biosimilars is patient education and reduction of anticompetitive messaging, she said. This can be achieved, in part, “by figuring out how to best exploit the educational gold mine of information that’s already available from real world experience with biosimilars. More than a decade of experience is available for some biosimilars in Europe, and at least several years of information should be available for some of the US-approved biosimilars.”

Yim noted the FDA’s achievement in modernizing the Purple Book, which originally was a bare bones listing of FDA-licensed biological products and now is an expanded, searchable, online database.

Also, in 2019, the FDA published guidance on biosimilar interchangeability with reference products and on the design and evaluation of comparative analytical studies for determining biosimilarity.

“We’ve made significant strides in advancing educational resources and activities and have recently begun a 2-year curriculum development project,” Yim said. “We also plan to begin work this year on developing additional, wide-reach education forums.”

Yim also said the FDA and the Federal Trade Commission have made “significant progress” combating anticompetitive behaviors by innovator companies and others that seek to oppose the advancement of biosimilars.

“Moving forward, we will be looking toward identifying and expanding high value activities that could help take biosimilar and interchangeable product access to the next level in the 2020s,” she said.

Articles

AAM GRx+Biosims

Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars (OTBB), highlighted the ways the FDA is working to remove blocks and wedges hindering biosimilars.  

OTBB Director Discusses FDA's Roadmap for Biosimilars

Investigators have presented evidence of what they say are successful, first-time tests of a multibiomarker disease activity (MBDA) score in patients with rheumatoid arthritis (RA). Separate comparative studies of infliximab and adalimumab biosimilars vs their reference counterparts were presented at the American College of Rheumatology (ACR) Convergence 2020 meeting.

The value of the MBDA score (Vectra) is that it consists of measures of 12 serum proteins and is highly sensitive, thereby offering an alternative to “subjective” clinical observation of patient progress, they explained.

“Comparison of MBDA scores between treatment groups may provide additional evidence of biosimilarity using an objective, quantitative assessment of disease activity that is independent of the potential subjectivity of joint counts or patient or physician global assessments,” said Jonathan Kay, MD, of the University of Massachusetts Medical School, who served as lead investigator for both studies.

Both studies involved Pfizer biosimilars and were sponsored by Pfizer.

In the first study, patients were randomized to treatment with an infliximab biosimilar (Ixifi) vs reference infliximab (Remicade) sourced from the European Union.

Investigators enrolled 650 patients who met 2010 ACR/EULAR disease classification criteria and had ≥ 4 months of RA duration. They received 3 mg/kg of infliximab intravenously at weeks 0, 2, 6 and then every 8 weeks, in combination with methotrexate (MTX). MBDA scores were on a scale of 1 to 100, with 100 being the highest level of disease activity. They reported initial treatment period activity for weeks 0 to 30.

Baseline mean scores for patients receiving the infliximab biosimilar were 61.3 vs 58.8 for the reference product. For the overall population, the mean scores at 30 weeks were 46.9 for both biosimilar and reference groups.

The proportions of patients with high MBDA scores at baseline in both the biosimilar and reference cohorts were similar: 66.0% vs 66.9%, respectively. At week 30, the proportions of patients with high MBDA scores decreased to 42.3% and 40.2%, respectively.

Investigators said the decreases in individual serum biomarker levels that formed the composite MBDA score also were similar between biosimilar and reference groups. They identified 3 biomarkers for which this was true—serum amyloid A, tumor necrosis factor receptor 1, and VEGF-A—but they said it held true also for other biomarkers included in the MBDA score.

Mean MBDA scores decreased 15.2 and 14.1 points, respectively from baseline to week 6 in the 2 groups, and disease stability between cohorts was noted through week 30.

In the second study, investigators enrolled 597 patients with RA by 2010/EULAR criteria and disease duration of ≥ 4 months. They were randomized to adalimumab biosimilar (Abrilada) or European Union–sourced adalimumab reference product and received 40 mg subcutaneously every other week, in combination with MTX.

Mean MBDA scores were calculated at baseline and weeks 6, 12, and 26. At baseline, the mean MBDA scores for the biosimilar and reference groups were 57.2 and 58.3, respectively. “Mean values of MBDA scores were comparable between treatment groups at all measured time points through 26 weeks,” the investigators wrote.

The proportions of patients with high MBDA scores decreased to 45.5% and 41.7% at week 26. Mean MBDA scores dropped from baseline by 11.9 and 12.4 points, respectively, by week 6; by 11.7 and 12.4 points at week 12; and by 14.3 and 15.5 points at week 26, respectively. Again, individual serum biomarker levels tracked one another closely between biosimilar and reference cohorts.

The mean scores over the 26 weeks for both cohorts were similar, leading adalimumab investigators to conclude: “MBDA score based on 12 serum biomarkers provides a sensitive and objective clinical assessment of biosimilarity that does not require physical examination of the patient or subjective patient global assessment of DA."

1. Kay J, alvarez D, Rehman MI, Zhang M, Iikuni N. Use of multi-biomarker disease activity scores to assess biosimilarity in a phase 3, randomized controlled trial comparing biosimilar infliximab-qbtx (PF-06438179/GP1111) with EU-sourced reference infliximab in patients with active RA. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 1204.

2. Kay J, Bock A, Iikuni N, Zhang W, Alvarez D. Use of multi-biomarker disease activity scores to compare biosimilar adalimumab-afzb (PF-06410293) with EU-sourced reference adalimumab in a phase 3, randomized, double-blind trial in patients with active RA. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 1233.

ACR Convergence 2020

A multibiomarker disease activity score looks at serum protein activity for a more sensitive evaluation of biosimilarity, investigators said at the American College of Rheumatology Convergence 2020 meeting.

Multibiomarker Test Reads Out Positive in 2 Pfizer-Sponsored Studies

Biosimilar developments reported at the American College of Rheumatology (ACR) Convergence 2020 virtual meeting included data from safety and efficacy trials for Pfizer and Celltrion versions of adalimumab.

Positive safety, immunogenicity and efficacy findings were reported for the Pfizer adalimumab biosimilar PF-06410293 (Abrilada, ADL-PF) in a study of patients with moderate-to-severe active rheumatoid arthritis (RA).

In an earlier study, ADL-PF, which has been approved in the United States and European Union, was compared with reference adalimumab sourced from the European Union (ADL-EU) and demonstrated therapeutic equivalence in patients with active RA. Comparable safety, efficacy, and immunogenicity was maintained up to week 56, and no differences in outcomes were observed for patients who underwent a blinded switch to ADL-PF at week 26.

At the ACR Convergence 2020, updated findings were presented for weeks 52 to 92 in patients who continued ADL-PF (N = 552). At week 52, all patients remaining on ADL-EU were switched to ADL-PF. Investigators said efficacy response rates at week 78 were 84.2% for all patients, and 83.4%, 85.8%, and 84.3% for the biosimilar, week 26 switch, and week 52 switch groups, respectively.

Investigators said response rates according to the ACR20 scale, which defines positive change as a 20% improvement in a core set of measures, were comparable across the 3 groups.

On safety, investigators said ADL-PF was generally well tolerated across groups with comparable safety profiles. With regard to immunogenicity, investigators reported comparable rates of antidrug antibodies (ADAs) and neutralizing ADAs.

In a separate study presented at ACR Convergence 2020, investigators demonstrated efficacy and safety equivalence of the adalimumab biosimilar candidate CT-P17 to reference adalimumab in patients with moderate-to-severe active RA.

CT-P17 is a high concentration (100 mg/mL), citrate-free formulation of the reference product. Investigators sought to show equivalence by efficacy at week 24 and by pharmacokinetics and overall safety over the first 24 weeks of administration.

Investigators randomized 648 patients 1:1 to reference and biosimilar adalimumab. They found that the ACR20 response rate at week 24 was 82.72% in both groups. Confidence intervals for treatment difference were fully within parameters set by the European Medicines Agency and the FDA. Secondary efficacy end points also were similar between cohorts.

Investigators noted a slightly higher serum trough concentration in patients receiving CT-P17 vs reference adalimumab at week 24: 5.3 μg/mL vs 4.3 μg/mL (

Safety profiles between groups also were similar. Most events were grade 1/2. Among the CT-P17 cohort (n = 324), there were 5 treatment-emergent adverse events leading to study discontinuation, vs 8 for the reference group (n = 324). Events leading to discontinuation considered related to the adalimumab treatment were 2 vs 4, respectively.

The number of patients who developed ADAs was lower at week 24 for those on CT-P17 vs reference (32.3% vs 35.8%, respectively). Among patients receiving CT-P17, 83 (25.6%) had neutralizing ADAs, vs 103 (31.8%) receiving reference product.

In March 2020, Celltrion applied for CT-P17 marketing authorization in the United States and Europe. Those applications are still pending.

1. Fleischmann R, Alvarez D, Bock A, et al. A randomized, double-blind phase 3 study comparing the efficacy, safety and immunogenicity of PF-06410293 (Abrilada™), an adalimumab (ADL) biosimilar, and reference ADL (Humira®) in patients with moderate to severe active RA: results from weeks 52-92. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0798.

2. Kay J, Jaworski J, Wojciechowski R, et al. A randomized, double-blind, phase 3 study to compare the efficacy and safety of a proposed high concentration (100 mg/mL) adalimumab biosimilar (CT-P17) with reference adalimumab in patients with moderate-to-severe active rheumatoid arthritis. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0800.

Poster presentations at the American College of Rheumatology (ACR) Convergence 2020 meeting shed light on performance of adalimumab versions. 

ACR Abstract Roundup: Pfizer and Celltrion Agents Demonstrate Safety, Efficacy

A study of Celltrion’s CT-P17 adalimumab biosimilar candidate demonstrated 

 and safety equivalence to US and EU samples of reference adalimumab

; and a separate study of difference administration methods for CT-P17 demonstrated equivalent outcomes

, in findings presented at American College of Rheumatology (ACR) Convergence 2020, the ACR’s virtual annual meeting.

Adalimumab reference product is indicated for arthritis, plaque psoriasis, ankylosing spondylitis, Crohn disease, and ulcerative colitis. CT-P17 was developed as a high concentration (100 mg/mL) citrate-free formulation of the reference product.

PK and safety of CT-P17 relative to US- and EU-marketed reference adalimumab were evaluated in a healthy population (N = 312) randomized to a single dose in each of the 3 arms.

Investigators said the 90% CI intervals for each of the PK parameters were within the predefined equivalence margin of 80% to 125%; and secondary PK parameters were similar among the 3 treatment groups. Mean serum concentrations up to day 71 were comparable among the trial cohorts, they said.

Investigators also described a comparable safety profile among the 3 cohorts. Most treatment-emergent adverse events (TEAEs) were grade 1/2. The most frequent of these was injection site reaction, but no clinically notable differences were observed in lab results, vital signs, electrocardiogram results, or physical examinations among the patient groups.

With regard to immunogenicity, patients testing positive for antidrug antibodies (ADAs) and neutralizing ADAs were comparable in each cohort. In addition, each group followed a similar curve as numbers of patients testing positive increased over the study term.

Investigators concluded that PK equivalence of CT-P17 relative to high concentration (100 mg/mL), citrate-free formulations of the US- and EU-samples of reference product was demonstrated. Safety was also comparable, they said.

In a separate, phase 1 randomized, single-dose study in healthy participants comparing PK and safety of CT-P17 auto-injector (AI) and prefilled syringe (PFS) products, investigators observed comparable findings for mean peak and total drug exposure as well as for secondary PK parameters, safety, and immunogenicity.

The trial randomized enrollees 1:1 to 40 mg of CT-P17 AI (n = 98) or PFS (n = 95). Investigators said 92 patients completed treatment on AI and 83 completed treatment with PFS.

In both groups, mean peak and total systemic exposure were equivalent because the 90% CIs were within the predefined equivalence margin of 80% to 125%, investigators said. Maximum dose duration (Tmax) occurred at 132 hours for both treatment groups. Secondary PK parameters also were comparable between the AI and PFS groups, as were mean serum concentrations.

On safety, 60.2% and 51.7% of patients reported ≥ 1 TEAE in the AI and PFS groups, respectively. There were 2 TEAEs (grade 3), and all other TEAEs were grade 1/2. TEAEs considered related to CT-P17 were reported by 47 (50.5%) and 38 (43.7%) of patients in the AI and PFS groups, respectively. The most frequent were headache (11.8% and 9.2%) injection site reactions (8.6% and 6.9%).

1. Pharmacokinetics and safety of CT-P17, a proposed high concentration (100 mg/mL) adalimumab biosimilar, in comparison with EU-approved adalimumab and US-licensed adalimumab; results of a phase 1, randomized, double-blind, three-arm, single-dose study in healthy subjects. Yu KS, Jang I, Lim HS, et al. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0204.

2. A phase 1, randomized, open-label, parallel group, single-dose study to compare the pharmacokinetics and safety of the auto-injector and pre-filled syringe of CT-P17, a proposed, higher concentration biosimilar (100 mg/mL) adalimumab, in healthy subjects. Keystone EC, Furst D, Kay J, et al. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0199.

Separate studies including one on application methods for CT-P17 were reported at the American College of Rheumatology Convergence 2020 meeting.

Celltrion's CT-P17 Adalimumab Biosimilar Candidate Demonstrates Equivalence

Following the launch of its Biosimilars Initiative in December 2019, Alberta, Canada, has succeeded in switching 16% of patients from use of 7 reference products to approved biosimilar versions, according to a presenter at the Terrapinn Festival of Biologics Basel 2020.

Alberta’s switching program launched 6 months after British Columbia began a similar initiative, which is further ahead with converting patients to biosimilars.

Alberta hopes to switch all patients on the 7 reference drugs to biosimilars by January 15, 2021, a deadline that was extended as a result of the coronavirus disease 2019 pandemic. Originally, authorities had hoped to complete the full conversion by July 1, 2020, said Graham Statt, the assistant deputy minister of the Pharmaceutical and Supplementary Benefits Division for Alberta Health, in the presentation.

According to a breakdown of the switching progress so far, 30% of patients receiving infliximab in Alberta switched to a biosimilar and 56% of those enrolled in a biosimilar patient support program.

Alberta officials hope the program will help save money on health care and improve access to biosimilars.

The 4 most frequently used reference products accounted for 75% of the province’s total net payment for biologics from 2019 to 2020, or US $200 million. Those products are Remicade (infliximab), Humira (adalimumab), Enbrel (etanercept), and Stelara (ustekinumab). In Alberta, there are etanercept and infliximab biosimilars available, but not for adalimumab and ustekinumab.

Also, the average annual growth rate of biologics 

use in Alberta over the last 5 years was 13.9%.

“Over the next 4 years, this initiative will save us between [US $173 million and US $290 million] once fully implemented. These savings will go back into the health system to help ensure we can provide the high-quality care Albertans deserve,” said Tyler Shandro, Alberta’s minister of health, in a 2019 

According to Statt, the Canadian province’s plan is 

 to British Columbia’s, where physicians are given a window of time to prepare patients for the switch from selected reference products to biosimilars. Physicians were encouraged to use research and educational materials to help manage patient concerns about medication changes. “We provided the numerous research and clinical studies on the efficacy and safety of switching patients from [originator] biologics to biosimilars, so people could be confident in the change,” said Statt.

The reference products that patients are being switched from include Remicade, Enbrel, Lantus (insulin glargine), Neulasta (pegfilgrastim), Neupogen (filgrastim), Copaxone (glatiramer), and Rituxan (rituximab). Alberta Health added Rituxan to its list after biosimilar Riximyo 

 regulatory approval from Health Canada in June 2020. Riximyo 

 across Canada in August 2020. Two other rituximab biosimilars, Truxima and Ruxience, were also added to the list of alternatives for Rituxan.

The switches aren’t mandatory. Statt clarified that according to the plan, patients enrolled in one of the Alberta Blue Cross government sponsored plans will no longer receive coverage for the reference product. Patients may submit an exception request to continue being administered the reference product, and if approved, pay out-of-pocket under their current plan policy or can change to another form of drug coverage under Alberta’s Blue Cross programs.

“I think this is actually an important point. We’re not forcing people to take a certain drug here in Alberta

. "What we're saying is that if you want to maintain coverage for the drugs, it has to be the drugs that we provide. In some cases, people may choose to stay on a particular drug, and they're welcome to do that."

As of early October, only 1.4% of patients had submitted exception requests and approximately one-fourth of those were approved, according to Statt.

In preparation for the switching deadline, he said that patients and physicians were sent reminder letters in October. Statt added that the next steps for the program include tracking patient drug usage, health outcomes of patients, and feedback from physicians and patients.

Alberta, Canada’s deadline for switching patients to biosimilars is months away, but the province has already seen some success with the new program.

Alberta, Canada, Sees Early Success From Switching Patients to Biosimilars 

There is much effort these days to conduct real-world studies of biosimilars, but findings from these initiatives are not really suitable for confirming safety and efficacy trials used to gain biosimilar approval, said Uwe Gudat, head of clinical safety and pharmacovigilance for Fresenius Kabi, a Germany-based maker of oncology, diabetes, critical care, digestive, and medical products, including biosimilars.

Real-world evidence (RWE) is better suited to answer questions about practical use of products in the real world, Gudat explained at the Terrapinn Festival of Biologics Basel 2020 virtual conference.

RWE cannot do the job of detailed physicochemical characterization and functional assays, he said. “Do we really think that real-world evidence can reassure us more than well-controlled randomized clinical trials? I don't believe so.”

The value of a clinical trial is that it screens out random variables, or “noise,” such as patient comorbidities, that distort whatever “signal” the biosimilar is giving that it can successfully treat the target disease conditions, Gudat said. You can’t get the same results in the real world, because there the background noise is strong, he said. “For the most part, when we’re answering questions, the signal clarifies and the noise distracts.”

In the clinical trial setting, the efficacy of a drug candidate is being evaluated; and in the real world, the actual effectiveness of the drug under conditions of everyday medical practice is being judged.

The analytical comparison of a biosimilar candidate done in a controlled setting can be compared to development of a car and the systematic testing of its constituent parts, he said. In the real world, “we’re taking the car out for a spin.” But it’s then that many other factors come into play. Continuing the car analogy, he explained that road conditions, driver fitness, driving skills, and time of day are variables that have the potential to “confound your comparison,” and the variations from what you observed in a controlled setting could be extreme and not the fault of your product.

Even in a drug trial, it is unlikely that clinicians will get the same results every time. It is a fundamental of statistics that patient outcome samples will vary, and these must be pooled to form a more comprehensive picture of how the biosimilar will perform, Gudat said.

He noted that clinical studies of US- and EU-sourced samples of reference adalimumab (Humira) have demonstrated variations that could be explained by local conditions under which the drugs were administered—not by variations between the US and EU biosimilars. “We don’t believe that studies conducted by one sponsor vs another sponsor are fundamentally different and the products used are fundamentally different; much more, we think there are certain circumstances that the study introduces that drive the observation,” Gudat said. "We have to acknowledge that there’s randomness."

Genuine product characterization involves pooling multiple samples of patient outcomes to form a statistical curve. Most of the samples will cluster in the center of this curve, but inevitably there will be outliers. The confidence interval, or the probabilistic margins of drug performance, cuts away the outliers, but those outliers still reflect what could happen when patients use the drug being studied, he said. “This is important, because it helps us understand what kind of numbers we’ll be looking at and what they mean or don’t mean.”

The real-world differences observed between US- vs EU-sourced Humira could be explained by non-drug–related variables, such as improper drug administration or the geographic dispersal of study populations and their epidemiological history—ie, tuberculosis, Gudat said.

For those reasons, he said, RWE doesn’t really help evaluate for biosimilarity. “It compares the products embedded in a multitude of circumstances. You have to look at the whole package. I’m really illustrating why the signal-to-noise ratio in the real-world setting is actually not necessarily conducive to generating comparative evidence for a biosimilar. You’ve just got so much noise; and if you do see a difference, you’ve got no idea where it’s coming from.”

That doesn’t mean RWE is of no value. There are questions that RWE can answer and should be used to answer, he said.

RWE studies can provide important information along the lines of who has gained access to the biosimilar, when is it being used in real world practice, how it is administered, and in what settings the biosimilar has been embraced, Gudat said.

By following this line of inquiry, real-world studies can complement clinical efficacy studies, he said.

Gudat suggested a number of potential real-world studies that would accomplish this objective:

Characteristics of patients treated with biosimilars

Health care practitioners’ attitudes and acceptance of biosimilars

Practitioners’ knowledge of biosimilars

Changes in the order of use of biologics (treatment lines)

Impact on patient outcomes (public health consequences)

“These are other questions equally important or also important that [RWE] can help us to answer,” Gudat said.

Festival of Biologics Basel

Expecting real-world evidence to confirm safety and efficacy of biosimilars is asking too much, Uwe Gudat, a pharmacovigilance expert from Fresenius Kabi, said at the Terrapinn Festival of Biologics Basel 2020.

Expert Cautions on What to Expect From Real-World Biosimilar Evidence

Orphan drugs are often significantly more costly than other biologics, and the presumption might be that biosimilar orphans could bring down the cost of these agents significantly, but the realities undermine that theory, said Roman Drai, MD, PhD, research and development director with Geropharm of Saint Petersburg, Russia.

However, it’s possible that with some modifications in evidence requirements by regulators, the cost of developing biosimilar orphans could be bought down significantly, and this savings could be passed on to patients, Drai said at the Terrapinn Festival of Biologics Basel 2020.

Under ordinary circumstances, competition helps to spur innovator companies to develop better drugs, with patients reaping the benefit, Drai said. “An innovator company might produce first-in-class and best-in-class drugs if they have someone pushing behind them, such as a biosimilar company.”

This doesn’t necessarily happen with orphan drugs, and the costs of development are the reason, Drai said. The costs of developing orphan drugs may be 4 times higher than costs for nonorphan drugs, he said. “The cost for ultra-orphan drugs could be 12 to 20 times higher.”

Orphan drugs are priced high in large part because they are intended for rare conditions and a small population of patients is eligible for treatment with these drugs. Further, the high costs of development must be offset within the same product exclusivity window as applies to common originator and biosimilar drugs, depending on patents, Drai said. This need for a return on investment is factored into the price of orphan drugs.

Another reason for the high cost of developing orphan drugs, both biosimilars and originators, is that for pharmacodynamic (PD) and pharmacokinetic (PK) studies, roughly 40 patients would be needed, but residual uncertainty needs to be resolved via efficacy, safety, and immunogenicity studies, and for this as many as 380 patients would be needed, he said. “You could not just enroll 50 patients to compare with a biosimilar; this is not enough to exclude the uncertainty.”

For that combined patient population (N = 420), an estimated $7.74 million would be needed to perform the PK/PD, efficacy, safety, and immunogenicity studies in Russia—roughly 7 times higher than for nonorphan drugs. In addition, those confirmatory studies would come after more basic studies to establish pharmaceutical and comparative quality and to perform comparative nonclinical evaluation.

Time is another factor that adds to the cost. Enrollment is prolonged because it isn’t easy to get patients to switch to a biosimilar for an orphan drug study, and enrollment may have to be conducted across multiple geographic zones to get the minimum number of patients. An immunogenicity study alone might stretch out to 12 months, Drai said.

Getting past these issues is possible with some structural changes in the way this development work is traditionally performed, he said. This can be accomplished by lowering residual uncertainty prior to phase 3 studies: Phase 3 studies could be waived altogether, they could be postponed until after marketing authorization, and a smaller-than-usual number of patients could be enrolled for phase 3 studies, Drai said, suggesting 3 alternatives.

The prerequisites for allowing such a bypass would be as follows: the existence of a simple molecular structure; high binding affinity between the molecule and antigen; low disulfide bridges; and moderate hydrophobicity, or molecular attraction to water. If these conditions are met, the phase 3 studies could be deemed unnecessary, Drai said.

Further, identifying biomarkers could ease the process by providing surrogate clinical end points for helping understand the drug’s mechanism of action, he said.

“We need to have smart approach to orphan biosimilars and develop guidelines for orphan biosimilars,” he said. “This would lower costs, and often a biosimilar orphan drug could cost less than an originator and it would make the therapy available all over the world.”

Biosimilar orphan drugs might not be cheaper than innovator orphan products, owing to multiple factors, but modifications to regulatory policy could change this, a presenter said at the Terrapinn Festival of Biologics Basel 2020.

Getting Orphan Biosimilars to Market at a Lower Price

Over 15 years of regulatory experience with biosimilar approvals, evidence has accumulated that phase 3 comparative efficacy studies may not yield useful data, panelists said at the Terrapinn Festival of Biologics Basel 2020. However, these studies play an important role in convincing providers to use biosimilars, they added.

Further, biosimilar immunogenicity studies also serve a doubtful role, and product drift, or variation in reference product quality over a period of time raises the question whether originator biologics should be subject to repeat testing over time to verify that they still meet the standards by which they were approved, panelists said.

The discussion was moderated by Lawrence Hill, chief development officer of Gan & Lee Pharmaceuticals in New Providence, New Jersey; and panelists included Sridevi Khambhampaty, vice president of Intas Pharmaceuticals in India; Bert Thomas, senior vice president of business development of Bio-Thera Solutions in China; and Sundar Ramanan, a global regulatory affairs executive with Biocon Biologics in India.

“The phase 3 studies may not really be essential for biosimilars,” Khambhampaty said. “A good amount of analytical similarity, coupled with a pharmacokinetic study, which proves the bioequivalence of the product, would be adequate for the licensure of some of the biosimilars, because the phase 3 studies are not really adding value in terms of demonstrating similarity.”

Analytical studies look at differences at the amino acid level. “There’s a whole battery of biological assays that speak to the efficacy of the molecule. With these high-resolution studies, it’s really questionable whether clinical efficacy studies would be able to find out more of importance,” 

However, she added that postmarketing studies can elucidate important characteristics of a biosimilar and how it’s really used in the real-world setting.

For these reasons, she voiced approval for a move toward less emphasis on clinical efficacy studies for biosimilar approval, as is being made by the UK Medicines and Healthcare Products Regulatory Agency. “We have to see how the other agencies across the world are going to embrace this. We have seen some movements in the insulin guidance from the FDA. They do not want to do phase 3 studies anymore.”

Hill responded that for generics these confirmatory efficacy studies traditionally have not been done, and doubts have been raised that generics are as effective as the originator products. If phase 3 efficacy trials were abolished for biosimilars, these drugs could be vulnerable to the same kinds of arguments by originator companies, he said.

“Arguments have to be backed by data,” Khambhampaty said. “There is adequate data for the safe use of biosimilars, and the wealth of data there is now for the biosimilars that have been in the market for 10 years would be adequate to argue against that.”

 studies are going to be adequate to demonstrate biosimilarity. But he noted that “by setting the bar high” and requiring comparative clinical efficacy studies, “it does give regulators some credence that biosimilars are what they say they are,” which is equivalent in safety and efficacy to originator products.

“Some doctors and patients don’t really understand the difference between small molecules and biologics and don’t really appreciate the nuances there,” he said. Efficacy studies help with the balancing act of getting biosimilars into circulation even if they don’t contribute much on the scientific level toward understanding the relative differences between originators and biosimilars, he said.

Hill agreed with the point, adding that the move toward a more purely scientific evaluation of biosimilars makes sense, but there’s always going to be “a small cohort” of doubters who want the efficacy studies.

Immunogenicity studies help to evaluate the immune response to a monoclonal antibody. The panel discussed whether these studies also contribute to the weight of useful scientific evidence. Although complex molecules, biosimilars are much more easily characterized than previously as science has advanced, and tweaks can be made during the manufacturing product to produce very precise changes, as needed, said Ramanan.

“We need to ask the question at this point in time what need is there for an immunogenicity study?” he said. “Data and knowledge should drive the amount of data required for a biosimilar to be approved.”

The decision whether to require these studies should be “judicious,” he added, because patients taking monoclonal antibodies are often in advanced stages of disease and their safety and well-being are critical. “The bar should be set high.” However, it does appear that scientific knowledge and process reliability have advanced to the point that “we can begin to move away from the immunogenicity study.”

Panelists noted that regulatory bodies may require biosimilar developers to conduct studies using biosimilar reference product source from the markets in which they will be marketed. For example, a developer may have to demonstrate equivalence to Herceptin (trastuzumab) from both Europe and the United States. In theory the reference drug should be the same no matter where it is sold. “It’s nonsensical,” Thomas said, noting the added time and expense needed to gather data that may be completely redundant.

However, from this argument comes the issue of product drift, or batch variation, Thomas noted that the assumption generally made is that the originator product is going to be the same. It has been demonstrated that reference product quality varies over time, which makes it more difficult for biosimilar manufacturers to hit the target on equivalence. 

“For us biosimilar manufacturers, it’s a huge issue.” Maybe originator products should be checked on a regular basis for consistency, he said.

Certain biosimilar studies are performed out of an abundance of caution and good marketing sense, although science has leapfrogged the need for these trials, panelists said at the Terrapinn Festival of Biologics Basel 2020.

Panelists Question Efficacy, Immunogenicity Studies for Biosimilars

Investigators from the University of Utah said they found no additional safety or clinical risks in a study of patients who were switched from originator infliximab to infliximab biosimilars. The participating institution, University of Utah Health Plans, achieved average savings of $11,508 per patient transitioned to a biosimilar.

The study findings are significant in part because health centers often start only new patients on biosimilars, for fear of destabilizing patients who have achieved disease control with the reference drug. The result is that for patients “grandfathered” to receive the reference product, the potential savings from biosimilars are forgone.

The strength of the study prompted the Academy of Managed Care Pharmacy (AMCP) Foundation to honor lead author 

 with the AMCP Foundation/CVS Health Best 

by a Resident or Fellow at the AMCP Nexus 2020 Virtual meeting on October 21, 2020.

Although multiple studies have demonstrated that switching patients with autoimmune disorders to an infliximab biosimilar is safe and efficacious, most physicians do not support nonmedical switching of patients who have achieved stability with the reference product Remicade because of concerns about effective management, patient mental health, and treatment safety and efficacy, the authors said, citing survey data.

Starting in February 2019, University of Utah Health Plans began switching all patients to biosimilar infliximab who were receiving Remicade originator infliximab. The primary end points were financial and clinical outcomes.

The study enrolled 63 patients (47.6% male, 52.4% female) ages 13 to 63 years. Savings calculations were based on the cost per 100 mg of the most recent Remicade infusion compared with subsequent biosimilar costs for the same patient. Patients included those with commercial (n = 42) and Medicaid coverage (n = 21), or 66.7% and 33.3%, respectively. Disease types included Crohn disease (47.6%), ulcerative colitis (17.5%), rheumatoid arthritis (12.7%), psoriatic arthritis (6.3%), and others.

A number of patients had been previously treated with other biologics, including adalimumab (29.5%) and etanercept (14.8%).

By April 2020, more than 90% of patients who began on the reference infliximab had been switched to a biosimilar. At a mean follow-up of 6.2 months, 44 (70%) of the 63 patients were on infliximab at the same or lower dose. Investigators said 9 patients had unstable or active disease before or after the switch and were given an increase in dosage or frequency of administration.

The savings for the health plan amounted to nearly $725,000, investigators said.

“Transitioning patients from the originator product to a biosimilar did not come with excess safety or clinical risks,” authors said. “The transition process included direct outreach via telephone to providers’ offices and was generally well accepted by all affected physicians.”

They said the findings suggest that the switching model could be applied to other patient populations. They recommended that in future investigations, patients be stratified by disease severity and treatment history to shed further light on the cost and cost and clinical efficacy relationship between reference infliximab and its biosimilars.

Parker T, Britton L, Willis C, et al. A retrospective analysis of the clinical and financial outcomes of converting patients from originator Remicade to an infliximab biosimilar. Presented at:

 AMCP Nexus 2020 Virtual; October 21, 2020. 

A study of mandatory switching for patients with rheumatologic conditions led to savings without effect on safety or efficacy.

Safety, Efficacy, and Savings Result From Study of Nonmedical Switching

Samsung Bioepis presented positive data from real-world switching and uptake studies of infliximab biosimilars in patients with inflammatory bowel disease (IBD) at the American College of Gastroenterology (ACG) 2020 Annual Scientific Meeting.

an 83% continuation rate among patients who were switched from reference infliximab (Remicade) to the biosimilar Renflexis. Investigators culled patient population data for the retrospective study from the US Veterans Affairs Healthcare System database.

The same study showed a similar continuation rate among patients who were switched from 

another biosimilar, to Renflexis, “reflecting the safety of switching from either reference product or biosimilar,” Samsung Bioepis said in a statement.

“Since IBD symptoms can be severe, maintaining a stable condition is important for IBD management. This study demonstrated that patients who were on infliximab, reference product or biosimilar, can remain stable after switching to another biosimilar, without major safety concerns,” said study leader Nabeel Khan, MD, an associate professor of clinical medicine at the University of Pennsylvania. 

that adoption of Renflexis, which became the preferred infliximab product on the Veterans Affairs National Formulary (VANF) in 2018, was faster than adoption of Inflectra. The latter became listed on the VANF in 2017, suggesting that providers are becoming more comfortable with the use of infliximab biosimilar agents.

“We are confident that this real-world switch data will provide additional reassurance to gastroenterologists who are treating patients with IBD,” said Seongwon Han, vice president and Medical & Lifecycle Safety team leader at Samsung Bioepis.

Renflexis was approved by the FDA in 2017. The goal of the first study was to augment data on the safety of switching in the real world. Patient data from January 2017 to May 2020 were included, and study requirements were that patients must have begun Renflexis prior to May 1, 2019, to provide sufficient follow-up. A minimum of 2 infusions of reference infliximab or Inflectra were required prior to initiating treatment with Renflexis, and patients must have switched to Renflexis after 3 months of stable IBD. The primary end point was Renflexis discontinuation at the 1-year point.

The investigators included 298 patients in the study and observed a 1-year Renflexis discontinuation rate of 17% (n = 52). They said 30 (10%) patients discontinued following cessation of response, which included development of resistant antibodies. Hypersensitivity led to discontinuation for 9 patients (3%).

The continuation rates for patients with a double medication switch (reference to Inflectra to Renflexis) and those with a standard single medication switch (reference to Renflexis) were similar: 82% and 87%, respectively.

The investigators noted that 13% of patients discontinued after loss of response or hypersensitivity reactions, leading them to conclude that switching from reference/Inflectra to Renflexis “through a single or double switch is relatively safe in a nationwide cohort of stable IBD patients.”

Rising Comfort Level for Infliximab Biosimilars

The second study described infliximab reference product use as the VANF policy transitioned to use of biosimilars. Again, the study looked at use of Remicade, Inflectra, and Renflexis. The originator drug was the preferred infliximab until May 2017, before it was replaced by Inflectra in that position from May 2017 to September 2018. Renflexis has held the preferred position since September 2018.

Patients with a treatment history may continue the nonformulary product under the VANF policy, but new patients must use the preferred product. These investigators studied 6 months of infliximab utilization data and found that infliximab products were used to treat 3488 veterans with IBD (60.2%, Crohn disease [CD]; 39.8%, ulcerative colitis [UC]) and the mean age was 52.5 years. Ninety percent of the patients were male.

The investigators said the mean time for the preferred formulary product to become the most commonly used product among veterans was 10 months for Inflectra and 2 months for Renflexis.

They said the percentage of patients treated with an infliximab biosimilar increased more than 800-fold (0.1% to > 86%) from the beginning to the end of the study. Prescribing patterns were similar in both UC and CD. The investigators noted no significant difference in utilization patterns for the various infliximab products, “suggesting that [Inflectra] and [Renflexis] are used in the same manner as [infliximab] originator.

They concluded that the rapid increase in use of these agents during the study period suggests that providers are becoming more comfortable with the use of biosimilar infliximab products in the treatment of IBD.

1. Pernes T, Patel M, Khan N. The safety of switching from originator infliximab or biosimilar CT-P13 to SB2 among a nationwide cohort of inflammatory bowel disease patients. Presented at: ACG 2020 Annual Scientific Meeting; October 23-28, 2020. P1597.

2. Johnson J, Sauer BC, Pinnell DK, et al. Infliximab biosimilar use for inflammatory bowel disease: a National Veterans Affairs experience. Presented at: ACG 2020 Annual Scientific Meeting; October 23-28, 2020. P1570. 

American College of Gastroenterology Annual Scientific Meeting

A retrospective analysis of data from the US Veterans Affairs Healthcare System database provides positive switching data for infliximab products.

Latest Conference Articles