Meir Rinde, MS, is a freelance print and radio journalist based in Philadelphia, Pennsylvania.

Meir Rinde, MS

Requiring patients to switch from originator etanercept (Enbrel) to etanercept biosimilars caused no permanent, unintended changes in patterns of health care use, suggesting the change did not harm patient health and may have even reduced disease severity, according to a Canadian study.

Health Canada approved the biosimilar products 

 (etanercept-szzs) in August 2016 and April 2017, respectively. This new study, by researchers at the University of British Columbia, tracked the effects of the first phase of the British Columbia Ministry of Health’s Biosimilar Initiative, which required patients to switch to biosimilars starting in May 2019.

Investigators used administrative data on prescriptions, diagnoses, hospital admissions and other events for 2655 individuals in the provincial health plan. They compared health services utilizations in the 3 years before the switch and during the policy implementation period. The most common diagnosis among patients in the study was rheumatoid arthritis (58.8%–63.1%), followed by psoriatic arthritis (12.6%–17.7%), juvenile rheumatoid arthritis, ankylosing spondylitis, and undetermined conditions.

During a 6-month transition period, the percentage of prescriptions for biosimilars among all etanercept refills covered by the provincial drug plan rose from 17.3% (349 of 2016 prescriptions) in May 2019 to 96.9% (1887 of 1948 prescriptions) in December 2019.

Among other results, the study authors found that the average quantity of etanercept dispensed and average number of days on other types of drugs were similar or lower in the policy cohort compared to the historical cohort.

“The direction of the change in utilization suggested a possible benefit,” they wrote. “Specifically, patients in the policy cohort had fewer days on [conventional synthetic disease-modifying antirheumatic drugs,] csDMARDS, oral steroids, and [nonsteroidal anti-inflammatory drugs], which may suggest better control of disease severity.”

The historical and policy groups also switched to different biologic DMARDs at similar rates, at 8.2%-9.7% for the historical cohorts and 9.6% for the policy cohort.

The authors observed anticipated changes during the transition, such as a transient increase of up to +0.9% in the cumulative incidence difference in first visits to physicians, and a transient increase of up to 1.7% in second visits. No difference was detected in third visits, while fourth visits had a transient increase of up to 2.6%.

For visits to rheumatologists specifically, the maximal cumulative incidence difference was an increase of 12.8% for first visits and an increase of 12.7% for second visits. No difference was observed in the cumulative incidence of emergency department visits or hospital admissions.

Other changes were minor or transient, including a transient increase (up to 3%) in first and second refills of etanercept during followup. There was no difference in third and fourth refills. By the end of the transition, 65.1% (1102) of the patients in the policy cohort had switched to a biosimilar, and 88.1% (1493) had done so by the end of a 1-year followup period.

The investigators noted different findings on health services use in similar studies of non-medical switches to biosimilars, many of which focused on treatment discontinuation. A Danish study found that the use and costs of outpatient services increased after switching to biosimilar etanercept, while costs of admissions and drugs decreased.

Studies of switches to biosimilar infliximab have found increased visits to physicians, including an 83% increase to rheumatologists and other specialists in an Italian study, and significantly higher health services costs in outpatient settings in a Turkish study.

“An increase in visits after switching…may have indicated unintended negative impacts of a policy. Further research with a design similar to the Danish studies could provide a better understanding of this change in British Columbia,” the authors wrote.

Fisher A, Kim JD, Carney G, Dormuth C. Rapid monitoring of health services use following a policy to switch patients from originator to biosimilar etanercept-a cohort study in British Columbia. 

2022;6(1):5. Published January 27, 2022. doi:10.1186/s41927-021-00235-x.

Articles

Health Canada approved biosimilars Brenzys and Erelzi in August 2016 and April 2017, respectively. The study tracked effects of the first phase of the British Columbia Ministry of Health’s Biosimilar Initiative, which required patients to switch to biosimilars starting in May 2019.

Making Patients in Canada Switch to Etanercept Biosimilars Caused No Harm or Changes in Health Care Use, Study Finds

Biosimilars markets are expanding rapidly around the globe due to growing demand and increasing production capacity, but governments across the Asia Pacific region, Latin America, and the Middle East and Africa must encourage more local manufacturing to increase access to treatment and lower costs, according to a set of papers by researchers in India.

 by Anurag S. Rathore and Ankita Bhargava of the Indian Institute of Technology in Delhi lay out the biosimilar approval guidelines and market growth projections for several countries in each region. Many governments have aligned their guidelines with those published by the World Health Organization (WHO) and the European Medicines Agency (EMA).

Asia represents 32.8% of the global market, with India, China, Malaysia, and Thailand offering well-developed regulatory pathways and showing strong demand. The Indian market is expected to climb from $2.2 billion in 2017 to $40 billion by 2030, thanks in part to considerable government subsidies. The Chinese biosimilars market is considered less mature, and it is projected to quadruple in value from $2 billion in 2018 to $8.1 billion in 2025.

Growth in Asia will be driven by factors including enormous unmet need in China, expansion of universal health care in Thailand, Indonesia, and other countries, and proliferating partnerships between global pharmaceutical companies and domestic manufacturers, the authors say.

“Most of the emerging economies are dependent upon major biologics manufacturers based in developed economies, something that has resulted in poor affordability and accessibility to this class of treatments. Most Asian countries…have established biosimilar regulatory pathways and are encouraging establishment of domestic development and manufacturing capabilities,” they write.

In Latin America, the market was valued at $517 million in 2018 and will exceed $3.9 billion by 2025, according to a recent market analysis. The top producer is Brazil followed by Argentina and Mexico, with a combined 44 similar biotherapeutic products (SBPs) in the 3 countries. In the trade bloc that includes Chile, Paraguay, Uruguay, and Venezuela another 18 products have been approved.

Latin American governments are promoting biosimilars to control spending as cancer, diabetes, and other chronic conditions become more prevalent, Rathore and Bhargava write. But the countries must strengthen their regulatory systems in the areas of pharmacovigilance, personnel training, data analysis, and guideline design, and support the establishment of more domestic producers, they say.

In the Middle East and Africa, the market was valued at $344.8 million in 2018 and was expected to grow to about $2.1 billion by 2025. Granulocyte colony-stimulating factor biosimilars are the most-used products, followed by insulin, interferon, and human growth hormone.

Nations with active biosimilar programs include Turkey, where 38 products are available, 13 of them produced in the country, and Egypt, where there are more than 55 products. Approved biosimilars in Saudi Arabia include Remsima, filgrastim, somatotropin, insulin glargine, and 4 oncology products. Nigeria has a local biosimilar production facility owned by a French pharmaceutical company.

Aging populations and increasing rates of diabetes and other high-cost diseases are driving the growth of Middle Eastern and African biopharma markets, but use of biosimilars is increasing slowly because few physicians are aware of them, the study says. The authors also note a burgeoning counterfeit drug market in Africa due to the high cost of biologics.

They call for government action to improve public trust in the drugs’ safety and efficacy; creation of clear legislation and pharmacovigilance systems; and assistance from WHO in the establishment of regulatory and risk management infrastructures.

Rathore AS, Bhargava A. Regulatory considerations in biosimilars: Asia Pacific regions. 

Rathore AK, Bhargava A. Regulatory considerations in biosimilars: Latin American region. 

Rathore AS, Bhargava A. Regulatory considerations in biosimilars: Middle East and Africa regions. 

Many governments have aligned their guidelines with those published by the World Health Organization (WHO) and the European Medicines Agency (EMA).

Authors Review Global Biosimilars Regulatory Landscape, Market Growth Projections

A bevacizumab biosimilar developed by Boehringer Ingelheim has comparable safety, efficacy, immunogenicity, and pharmacokinetics to the reference product in patients with recurrent or metastatic non-small cell lung cancer (NSCLC), according to a new study.

In a phase 3 trial of BI 695502, the primary end point of best overall response rate (ORR) until 18 weeks was 54% in the group receiving the biosimilar and 63.1% in the bevacizumab RP (Avastin) group. The study demonstrated a 90% confidence interval (CI) for the primary efficacy end point falling within the prespecified range, the authors say.

Similar efficacy and toxicity have been observed in clinical studies of other bevacizumab biosimilars compared with bevacizumab RP. Two biosimilars, Pfizer’s Zirabev and Amgen’s Mvasi, have been approved for indications including unresectable, locally advanced NSCLC and recurrent or metastatic nonsquamous NSCLC. BI 695502 is no longer under development by Boehringer Ingelheim.

“Studies like the one reported here are…integral to the increased use of biosimilars across a range of indications,” the authors write. “These results enrich the evidence that bevacizumab biosimilars are a safe and efficacious alternative to bevacizumab RP.”

The trial screened 1030 patients at 190 locations, and randomized 671 patients from 161 centers in 28 countries between July 2015 and November 2018. They received up to 18 weeks of induction treatment with BI 695502 or bevacizumab RP 15 mg/kg plus paclitaxel and carboplatin. Slightly more patients in the BI 695502 group had ECOG PS of 1 (63.0% versus 60.4%), and slightly more patients had brain lesions (6.6% versus 3.7%) than in the bevacizumab RP group.

After a manufacturing issue with one batch of the biosimilar in December 2017, investigators switched the 13% of patients who had not yet completed maintenance to bevacizumab RP. Comparisons of the 2 products were based primarily on preswitch data.

The 90% CI for the between-group ratio of best ORR (0.770 to 0.951) was within the prespecified range for equivalence (0.736–1.359). The 95% CI for the ratio of best ORR (0.754–0.970) also fell within the required range (0.727-1.376) to satisfy the Japanese and European regulatory criteria for equivalence.

Median progression-free survival was 8.3 months in patients receiving BI 695502 and 9.0 months in those treated with bevacizumab RP (HR = 1.22, 95% CI: 1.02–1.45). Median overall survival was 15.6 months in the biosimilar treatment group and 19.5 months in the RP group (HR = 1.23, 95% CI: 1.00–1.51).

Plasma concentrations were slightly higher in the bevacizumab RP group, but the differences were not considered clinically relevant. Among patients with negative or unknown anti-drug antibody (ADA) status at baseline, 4 patients (1.2%) in the BI 695502 group and 8 patients (2.4%) in the bevacizumab RP group had at least 1 positive ADA result post-baseline.

The proportions of patients with at least 1 adverse event (AE) and with drug-related AEs were similar in the 2 groups during the preswitch period. The most common AEs were similar and occurred at slightly higher frequency in the biosimilar group. All-cause and drug-related grade 3/4 AEs occurred in a higher proportion of patients in the BI 695502 group compared with the bevacizumab RP group.

Among the AEs leading to death, they were drug-related in 4 patients in the BI 695502 group and 2 patients in the bevacizumab RP group. Signs and symptoms of immunogenicity were rare.

AEs of special interest (hepatic injury, anaphylactic reactions, GI perforations, pulmonary hemorrhage) were reported in a higher percentage of patients in the BI 695502 group (3.6%) compared with the bevacizumab RP group (0.9%). The 95% CI of the risk ratio (BI 695502/bevacizumab RP; the calculated value of 1.16) was 0.99 to 1.37, indicating the treatments were comparable.

Kim ES, Balser S, Rohr KB, Lohmann R, Liedert B, Schliephake D. Phase 3 trial of BI 695502 plus chemotherapy versus bevacizumab reference product plus chemotherapy in patients with advanced nonsquamous NSCLC. 

2021;3(1):100248. doi:10.1016/j.jtocrr.2021.100248

Two biosimilars, Pfizer’s Zirabev and Amgen’s Mvasi, have been approved for indications including unresectable, locally advanced NSCLC and recurrent or metastatic nonsquamous NSCLC. BI 695502 is no longer under development by Boehringer Ingelheim.

Phase 3 Study Shows BI Bevacizumab Biosimilar Comparable to Reference Product

Developers can bring biosimilars to market more quickly and at lower cost by challenging regulatory requirements and restricting testing of these agents to analytical similarity and clinical pharmacology, Sarfaraz K. Niazi, PhD, writes in a December 2021 paper in the journal 

Niazi is an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, founder of the biosimilars companies Karyo Biologics and Adello Biologics, and a Center for Biosimilars® Advisory Board member.

After analyzing regulatory documents for over 100 biosimilars, Niazi concluded that excluding the other main processes contributing to approvals—animal testing and clinical efficacy testing—would not have changed any approval decisions.

Niazi, who has previously challenged FDA and World Health Organization biosimilar approval guidelines, says the agencies will not reject rational scientific plans that dispense with tests that do not provide helpful information. They have modified and relaxed many requirements in recent years, he says.

“While the agencies may be slower in changing their guidelines, the onus lies on the developers to challenge the guidelines to restrict the testing to analytical similarity and clinical pharmacology. Even these testings can be reduced significantly without compromising their value to establish biosimilarity,” he writes.

Future challenges will lead to “a new era of faster, lower-cost approval of biosimilars without risking their safety and efficacy,” he says.

Animal testing is not helpful for biosimilar approvals because differing animal and human pharmacodynamics mean toxicology studies do not provide useful data, Niazi says. No biosimilars have failed in animal toxicology testing, “because they cannot.”

In the past, the FDA has often declined to evaluate animal studies of biosimilars, and its Center for Drug Evaluation and Research is now encouraging use of new approach methodologies, he writes. Alternative approaches include human and animal cells, organoids, organ-on-chips, and in silico modeling.

Organoids are multicellular constructs that mimic the activity or tissue environment of human organs. Organ-on-chips are devices that mimic the human physiological and mechanical environment for the purposes of medical study, and in silico models are digitized representations of pharmacologic and physiologic processes.

Niazi provides several arguments why developers should avoid clinical efficacy studies. Comparing supposedly identical products is “a statistical challenge” based on “arbitrary assumptions,” he writes. The FDA allows use of pharmacokinetic and pharmacodynamic (PD) biomarker data in healthy patients instead, which generally requires shorter, less costly studies and produces more sensitive results. The agency has already licensed several products on PD evaluation only.

Efficacy testing is mostly “a checkmark item” that “constitutes unnecessary human exposure,” he writes.

He says clinical studies of comparative equivalence are not useful, as they are unlikely to fail and have never resulted in the rejection of biosimilarity. They are also difficult to conduct for some drugs for which recruitment of homogeneous populations or comparable patients is a challenge, such as anticancer agents.

In the future, regulators will approve biosimilars based solely on analytical assessment and clinical pharmacology profiling, Niazi argues. These areas can also be made less complex. He advises developers to avoid orthogonal testing during analytical assessment and follow agency recommendations that they explore creative methods, such as using ultraviolet and fluorescence spectroscopy to compare secondary and tertiary structures.

Novel testing modalities should also be considered for clinical pharmacology comparisons. Niazi suggests keeping to narrow criteria for study subjects in order to reduce study sizes. He also recommends consolidating all expected outcomes in a single study, while at the same time avoiding unnecessary meetings with FDA officials to prevent development plan delays.

Niazi SK. Biosimilars: a futuristic fast-to-market advice to developers. 

. Published online December 27, 2021. doi:10.1080/14712598.2022.2020241

In a recent paper, Sarfaraz K. Niazi, PhD summarizes some of his central ideas on the relevance of FDA biosimilar testing standards.

Developers Advised to Challenge Regulatory Standards to Speed Development of Biosimilars

The approval of biosimilars of granulocyte colony-stimulating factor (G-CSF) and of a new injection device contributed to increased use of G-CSF among patients with cancer with a high risk of febrile neutropenia (FN), but many eligible patients still do not receive the preventive treatment, according to a new study.

G-CSF is a growth factor that helps the bone marrow to regenerate white blood cells following myelosuppressive chemotherapy and to ward off infection.

From 2014 to 2019, use of G-CSF to prevent FN in high-risk patients rose from 75% to 83% for the commercially insured population and from 75% to 86% for the Medicare population, according to the research published by University of Florida investigators in 

Older age, receiving a high–FN risk regimen, and history of neutropenia were associated with use of G-CSF.

However, as of late 2019, 14% to 17% of patients with high FN risk who were on chemotherapy still did not receive the preventive treatment, despite National Comprehensive Cancer Network (NCCN) guidelines recommending they receive primary prophylaxis using G-CSF.

The study authors note the NCCN has offered short-term guidance expanding recommended uses for G-CSF. The organization stated that in the context of the COVID-19 pandemic, clinicians may consider giving prophylactic therapy to patients receiving intermediate-risk regimens.

There are 2 G-CSF products for which biosimilars are available: Neupogen (filgrastim) and Neulasta (pegfilgrastim). During the study period, the filgrastim biosimilars Zarxio and Nivestym came on the market. A third competing filgrastim product (Granix) also launched, although this is not officially a biosimilar, as it was approved under a different regulatory pathway.

Two pegfilgrastim biosimilars were approved and launched during the study period: Fulphila and Udenyca. The Onpro, a wearable injector pegfilgrastim device, also was launched, and this has a roughly 50% share of the market for pegfilgrastim. Onpro uses the reference product (Neulasta), not a biosimilar, and there are no wearable injector biosimilar G-CSF devices on the market.

“The availability of biosimilar G-CSF presents an opportunity to reassess the cost-effectiveness of prophylactic G-CSF use in patients receiving myelosuppressive chemotherapy regimens. Evidence shows that using biosimilar G-CSFs for primary prophylaxis among patients with intermediate risk can be a cost-effective strategy even without risk factors,” the authors wrote.

Practice-improvement policy initiatives, along with decision support tools meant to reduce overutilization and inefficient practices, may have driven observed decreases in G-CSF use among patients receiving intermediate– or low–FN risk regimens in the commercially insured population, the study authors say.

Several biosimilars of the G-CSF products filgrastim and longer-acting pegfilgrastim were launched between 2015 and 2019, and the Onpro wearable injector was launched in 2017, expanding treatment options for patients.

The study, which examined 119,129 courses of chemotherapy given to patients with cancer from 2014 to 2019, found use of the filgrastim biosimilar Zarxio surpassed that of the filgrastim originator. The biosimilar accounted for 55.6% of all short-acting G-CSF use in the commercially insured population in the fourth quarter of 2019 and 22.2% of all short-acting G-CSF use in the fourth quarter of 2018 in the Medicare population.

In two nationally representative samples, there was increased G-CSF use among patients with high FN risk from 2014 to 2019 in a commercially insured population and from 2014 to 2018 in the Medicare population, but 14% to 17% of patients with high risk did not receive prophylaxis.

Among all long-acting G-CSF use in the last observable quarter of each data source, Onpro accounted for 44.9% of use in the commercial insurance data and 52.4% in the Medicare data. Pegfilgrastim biosimilars saw rapid initial uptake, accounting for 29.8% of all long-acting G-CSF use in the fourth quarter of 2019 in the commercially insured population.

The investigators note the G-CSF market is dominated by long-acting products, primarily the Onpro delivery service, where biosimilar uptake is lower than with short-acting therapy.

“Preference for the [Onpro] device may limit the adoption of long-acting biosimilar G-CSF products and undermine the potential cost savings implied with biosimilar availability in this therapeutic area. While a simulation study has demonstrated cost savings from biosimilar adoption, a variety of barriers exist,” they wrote.

For example, a biosimilar may not cut costs for patients considering the need for a second visit to a clinic and associated costs.

The authors say biosimilar device development or more aggressive reimbursement or formulary structures may be needed to drive use of G-CSF biosimilars. Future studies that use real-world data to show the cost savings from pegfilgrastim biosimilars could strengthen payer and clinician confidence and facilitate broader adoption, they say.

The arrival of biosimilars for filgrastim and pegfiltrastim coincided with higher use of granulocyte colony-stimulating factor (G-CSF) for prophylaxis against febrile neutropenia, but many high-risk patients still do not receive the treatment.

Study: High-risk Population Still in Need of G-CSF Biosimilars

for biologics and biosimilars that incorporated price competition would have reduced spending on 6 biologics by 27%, or $1.6 billion, from 2015 to 2019. Adopting this model in the future could lead to substantial savings, according to researchers at a health care policy think tank.

Biologic therapies account for most of Medicare Part B’s prescription drug spending and spending growth (80% of spending in 2017 and 92% of spending growth from 2006 to 2017), according to the study in

 by Sean Dickson, director of health policy at West Health Policy Center in Washington, DC, and Tyler Kent, a data scientist formerly with the West Health Institute in La Jolla, California.

Despite these findings, price decreases of biologic and biosimilar products in Medicare Part B have been minimal, even with biosimilar competition, they write.

The researchers attribute the lack of price drops to Medicare’s policy of reimbursing for biologics and biosimilars at 100% of each therapy’s average sales price (ASP) plus 6% of the reference product’s ASP, which they say encourages clinicians to select the highest-cost option for the greatest reimbursement.

Proponents of the current system of 100% plus 6% of the reference drug’s ASP contend it removes the bias toward using the higher-cost product. The Community Oncology Alliance, an association of independent oncology practices, has 

 that a common reimbursement code for reference products and biosimilars would encourage “race-to-the-bottom” pricing that would make drug supply chains unstable.

Given the relatively low uptake of biosimilars in the Medicare Part B program and the lack of incentives for drug manufacturers to compete on price, the current policy appears to be insufficient in encouraging appropriate competition and price reduction.

By comparison with biologics, brand-name and generic drugs are reimbursed at 106% of the weighted ASP of the brand-name and all approved generic products, incorporating the lower generic drug prices into the reimbursement and encouraging clinicians to select the lowest-cost option.

The authors advocate a bundled biosimilar reimbursement model that would similarly reimburse both innovator biologics and biosimilars under a single billing code. They calculate it would have reduced spending on 6 top biologics—filgrastim (Neupogen), infliximab (Remicade), pegfilgrastim (Neulasta), bevacizumab (Avastin), trastuzumab (Herceptin), and epoetin alfa (Epogen)—by $1.1 billion over 4 years, while lowering spending on biosimilars by $500 million.

They also estimate that adopting a related, least-costly alternative reimbursement policy would have saved between $1 billion to $7.5 billion in 2020.

“This potential for substantial, greater future savings emphasizes the importance of rapidly implementing the bundled biosimilar reimbursement model to take full advantage of the price reductions that are associated with new biosimilar entrants,” they write.

“Moreover, rapid adoption would encourage additional biosimilar development, as biosimilars would be better able to compete on price under the bundled biosimilar reimbursement model compared with the current policy."

About $1.3 billion of the savings on the 6 therapies would accrue to the Medicare Part B program, which covers drugs administered by clinicians in an outpatient hospital or clinic setting. The remaining $300 million would offset beneficiary cost sharing, which would reduce costs for Medigap insurance plans and eventually lead to lower premiums, the authors say.

They note that the pharmaceutical industry argues the current billing code system for biologics and biosimilars is needed to incentivize biosimilar development and marketing. But they argue that “given the relatively low uptake of biosimilars in the Medicare Part B program and the lack of incentives for drug manufacturers to compete on price, the current policy appears to be insufficient in encouraging appropriate competition and price reduction.”

Researchers report findings that suggest a different reimbursement system for Medicare Part B biologics could lead to significantly more robust savings. 

Study: Medicare Consolidated Biosimilar Payment Codes Would Save Money

 to advise manufacturers how to minimize or avoid clinical trial requirements encountered challenges from the lack of mature quality data that applicants could provide, but participants nonetheless valued the feedback process and the agency will continue offering developers “tailored” scientific advice, the EMA said in a report.

Tailoring the development of biosimilars is of growing importance in light of the advances in knowledge and the emergence of more precise technologies for determining bioequivalence. Protein mass spectrometry, for example, is 10-million-fold more sensitive than it was a decade ago, and comparative clinical trials are now viewed as imprecise tools for determining likeness between biological agents.

The quality data submitted by 4 applicants were immature for reasons such as the limited number of batches or because the data were not obtained with material from the proposed commercial process, the report said.

That made it difficult for reviewers to make recommendations on questions such as the number and population of patients and the efficacy margins required for clinical trials.

A key insight of the pilot was that the regulatory guidelines anticipated a “stepwise” approach to comparability studies, in which early uncertainties about biosimilarity are used to determine whether and which further analyses are required. In reality, however, that analytical process occurs at the same time as clinical development, the report said

“Employing such tailored scientific advice requires adaptations in development by having a mature quality and in vitro nonclinical data package prior to the conduct of animal or clinical studies, in order for its utility not to be restricted to simple scientific advice ‘quality checks’ on the available data throughout the development,” the agency said.

For the pilot, which ran from February 2017 to April 2020, the Scientific Advice Working Party, Biologics Working Part, and Committee for Medicinal Products for 

Human Use agreed to conduct a more extensive scientific review than is standard.

The reviewers could give advice on differences identified at the quality level and their potential impact on the suitability of the biosimilar approach or on the need for and design of additional preclinical or clinical investigations. They could also advise whether a simplified clinical development program, such as a waiver of a clinical trial, could be granted.

Four applicants submitted 6 requests regarding biosimilar monoclonal antibodies, with one submitting 2 separate development plans and another requesting initial and follow-up advice for the same plan. The latter applicant’s second submission had a more “mature and comprehensive data package,” the report said. One applicant was a small/medium-size enterprise.

The advice given had, in most instances, more impact on the generation of quality data per se and less impact on clinical data requirements than anticipated. It would therefore need to be seen how biosimilar development programs can be adapted to allow potentially reduced animal and clinical study requirements.

Eight other prospective applicants expressed interest in participating. Over the same period, the agency also received 71 requests for standard advice on biosimilars.

The report said the participants appreciated the opportunity to discuss their quality comparability data with regulators and considered the comprehensiveness of the advice “very important” to gain clarity and confidence in their biosimilar programs. However, due to the immaturity of the data, the advice ultimately given had more impact on the generation of data and less on clinical data requirements than anticipated.

Thus it still remains to be seen “how biosimilar development programs can be adapted to allow potentially reduced animal and clinical study requirements to be considered,” the agency said.

EMA will continue to offer tailored scientific advice as part of its regular operations, in order to further develop the advice process using specific cases and to allow the continuation of useful scientific discussions.

The report noted that the pilot completed 6 sets of advice, as planned. The initial uptake was slower than expected, which the agency said is not unusual for new types of engagement opportunities.

Asked how well their expectations for tailored scientific advice were met, 4 applicants who responded to a feedback questionnaire gave an average rating of 3.7 of 5.

The World Health Organization is currently revising guidelines for biosimilar development, in part to incorporate a tailored approach. The Center for Biosimilars

, policy and science officer for Medicines for Europe, a trade organization, about the value of this process for bringing more competition to markets for orphan drugs and other therapeutics. 

European Medicines Agency (EMA) officials said their pilot was based on wrong assumptions about the biosimilar development process. 

EMA Reports on Pilot Study of Biosimilar Development Tailoring 

A study from a free market–focused think tank argues for the elimination of market barriers to biosimilars to tap potentially billions of dollars in health care system savings that biosimilars for 2 widely used drugs could provide.

 from the Pacific Research Institute (PRI) in California analyzed the potential impact of biosimilars for AbbVie’s adalimumab (Humira), the top-selling drug in the United States, and Amgen’s etanercept (Enbrel). Both therapies treat rheumatoid arthritis and other autoimmune conditions.

Annual systemic savings could total up to $5.8 billion, with $4.7 billion resulting from biosimilars for Humira and $1.1 billion from drugs that are interchangeable with Enbrel, said Wayne Winegarden, PhD, director of PRI’s Center for Medical Economics and Innovation and the study’s author.

“These calculations emphasize the importance of promoting an environment that empowers competition once the originator’s exclusivity period has expired. These reforms include eliminating barriers such as rebate walls and promoting positive reforms such as favorable formulary tiers for biosimilars,” Winegarden wrote.

The estimate is based on the maximum savings possible if new biosimilars for the 2 drugs were to achieve a 75% market share. The total savings would reach up to $3.9 billion at 50% market share, and between $1.3 billion and $1.9 billion at 25% market share.

Neither drug currently faces competition from biosimilars. Amgen has said it plans to begin marketing adalimumab (Amjevita), the European Union’s best-selling adalimumab biosimilar, in the United States in 2023. A commercial license for Boehringer Ingelheim’s adalimumab (Cyltezo) will begin in 2023, according to the company.

The FDA has approved 2 Enbrel biosimilars, Sandoz’s etanercept (Erelzi) and Samsung Bioepis’ etanercept (Eticovo), neither of which is available in the United States due to patent issues.

AbbVie’s Humira generated $16.11 billion in gross revenues and Amgen’s Enbrel earned $4.86 billion in 2020, according to the PRI study.

To the extent that the net prices of Humira and Enbrel increase before the introduction of competition, then the potential savings enabled by biosimilar competition would increase.

However, after considering rebates, fees, and discounts that the manufacturers pay, and projecting the change in sales from last year, Winegarden projected that the health care system will spend $10.3 billion on Humira and $2.5 billion on Enbrel doses in 2021.

The study used 3 scenarios for drug price discounts—40%, 50%, and 60%—that could occur if biosimilars for the drugs were available, and modeled the resulting ranges of systemic savings at different levels of market share gain.

Breaking the figures down by payer, commercial payers could save up to $2.9 billion for Humira and $707 million for Enbrel, state Medicaid programs could save up to $875 million and $214 million, respectively, and federal expenditures on Medicare and military insurance could decrease by up to $726 million and $175 million, respectively, the study estimated.

Payers in every state would benefit. The states with the highest projected savings are Florida, which would see spending reductions of $77 million to $347 million depending on the discount rate scenario and level of market share gain, and Pennsylvania, where the savings could fall between $78 million and $349 million.

“These calculations demonstrate that an environment that successfully fosters biosimilar competition in just these 2 biologic drug classes will generate significant systemic savings that will meaningfully improve the current drug affordability landscape,” Winegarden wrote.

The conservative think tank Pacific Research Institute (PRI) calculated potential biosimilar savings across multiple market share scenarios. 