Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

China has just 9 biosimilars approved vs 29 in the United States, and the United States is expected to stay ahead in this race through 2027. However, fundamental regulatory reforms in China have established a framework for biosimilar development and approval that will encourage robust competition in that market, according to a recent presentation by intellectual property (IP) attorneys from Goodwin Proctor.

“The regulation of research and development and the registration pathway for biosimilars in China will continue to become more structurally sound, clear, and transparent in the foreseeable years,” said Freddy Yip, PhD, PCLL, a Hong Kong–based attorney.

By US standards, there were once no true biosimilars in China, owing to lesser standards for approval, but regulatory policies have been tightened up considerably. In 2015, China created a standardized regulation for the development and evaluation of biosimilars, which Yip and Huiya Wu, JD, described as key to the biosimilars regulatory revolution in China. This clarified the definition of biosimilars and set standards for preclinical research and development, clinical trials, and manufacturing processes, creating what Yip said was the “foundation” for growth of China’s biosimilars industry.

In tandem with the various regulatory initiatives, China provided impetus to the biologics market by adding many biologics to the national reimbursed drug list (RDL). Up until 2017 this list included chemotherapy treatments but not oncology biologics, Yip said. “As a result, prices of these drugs decreased significantly, and as more biologics are included in the RDL, the affordability of biologics is expected to increase, which allows greater market access.”

The country since 2018 has allowed priority review and approval for drugs that address urgent clinical needs and potential clinical trial exemptions for drug applications supported by robust clinical data from trials conducted overseas, Yip said.

Consequently, the China market for biologics has grown from $18 billion in 2014 to $40 billion in 2018, and the projection is for a $99 billion market to emerge by 2023, the attorneys said, citing Frost & Sullivan data. As in the United States, growth of the biologics market in China has broadly eclipsed the generics market expansion there. Yip predicted that in China, where there is much greater acceptance than in the United States for use of nonoriginator brands of medicine, the growth rate for biosimilars will soon “be much larger” than for their reference drugs.

In the United States, the biosimilars market in 2019 was $737.2 million vs $354 million in China. Strong growth is projected in both markets, but “it appears that the United States will continue to be the larger market through at least 2027,” Wu said.

It takes more time to get a biosimilar through the approvals process in the United States than in China, Wu said. Development time in China might take 5 years or more and cost upward of $50 million, vs 7 to 8 years and $75 million to $250 million in the United states, she estimated.

Another key characteristic that defines the China market for biosimilars is the dominance of relatively small biopharmaceutical companies, Wu said. In the United States, “for the most part, these are big-pharma, well-established companies, although there are smaller, newer companies, like Coherus BioSciences. There’s also a pretty strong representation by Republic of Korea companies like Celltrion.”

The China market may lack the representation of these large players, but its biosimilar companies have the advantage of intellectual property laws that may allow earlier entry of biosimilars. This has been the case for adalimumab (reference, Humira). The first adalimumab biosimilar in China was launched in January 2020 by Bio-Thera Solutions. The first US biosimilars for adalimumab are prevented from launching until 2023 owing to settlements between originator company AbbVie and biosimilar developers.

Although China-based companies hold all of the approvals so far for biosimilars in that market (

), outside companies are partnering with China companies to gain the insight and leverage they need to penetrate that market and get a share of the growth. This includes Amgen, of Thousand Oaks, California, which has established a collaboration with China-based Simcere; and Samsung Bioepis, a Republic of Korea–based company working with China-based 3SBio. Celltrion hopes to build what will be China’s largest biologics manufacturing facility in Wuhan.

China’s drug approval process has been significantly accelerated, Yip explained. Henlius began preclinical development for its rituximab biosimilar in 2010 and filed its investigational new drug application (IND) in 2011 (requesting permission to begin phase 1 in-human trials). It finally received IND approval from the National Medical Products Administration (NMPA) in 2014. In 2017 it filed a new drug application (NDA) with the NMPA and received NDA approval in 2019, becoming the first company to land an official biosimilar approval in China.

Today, that process would take substantially less time, depending on the quality of the application. “Each of the timeframes [from IND application to drug marketing authorization] is now measured in days, with the single longest step taking only 90 days,” Yip said. “For example, if an IND applicant does not receive any negative or questioning opinions from the NMPA within 60 days of the date of application acceptance and payment of the fee, clinical trials may be conducted in accordance with the plan that has been submitted.”

In 2018 and 2019 the Chinese government identified 78 priority drugs for which approval processes could be expedited and overseas clinical trial data used to support the applications. This was done to encourage pharmaceutical companies to bring these drugs to market as quickly as possible.

In general, Chinese regulators require in-country clinical trials that demonstrate drugs have been tested for safety and efficacy in Chinese populations. Now, “If there is no ethnic difference in the clinical study, sponsors can submit the clinical trial data obtained overseas and directly apply for the drug listing registration,” Yip said.

Articles

It took Henlius years to get a rituximab biosimilar approved in China. Now, that process could be cut in half, owing to significant regulatory reforms. 

China Pulls Out Stops for Biosimilar Development

The past year was “turbulent” for the health care industry, and sales of Coherus BioSciences' pegfilgrastim product (Udenyca) were not what the company had hoped. But as the pandemic wanes, the company anticipates a change in market dynamics that will enable the product to achieve greater market share, according to Dennis M. Lanfear, president and CEO of the Redwood City, California, company.

Udenyca launched in 2019 and has achieved a roughly 20% share of the pegfilgrastim market, Lanfear said in a presentation at the 39th Annual JP Morgan Global Healthcare Conference. Coronavirus disease 2019 (COVID-19) gave a rival product a boost that denied Udenyca a greater share of the market it might otherwise have attained, he said. Pegfilgrastim is used to fight off infection associated with chemotherapy treatment. 

Amgen’s Neulasta Onpro on-body injector, launched in 2015, enables patients to receive pegfilgrastim injections at home, saving them from having to visit clinics battling to prevent the spread of COVID-19. By midyear 2020, Onpro had accumulated a 58% 

In his presentation at this year's virtual J.P. Morgan Health Care Care Conference, Lanfear predicted that vaccinations will enable patients to return to clinics for vaccinations and use of the Onpro will diminish, creating market opportunity for Udenyca. 

The chief value of Onpro is its convenience for home use, although a recent study recorded 

 from 1.7% to 6.9%. “We expect that as COVID-19 wanes, market gains at the expense of [the] Onpro share are expected to resume,” Lanfear said.

From its launch in January 2019 until September 30, 2020, Udenyca has achieved $720 million in revenues, Lanfear said. There are now 4 pegfilgrastim biosimilars on the market; most recently, Pfizer’s Nyvepria was launched in December 2020. Amgen’s originator pegfilgrastim products, including Onpro, control about 70% of the market. Although Lanfear predicted that Udenyca’s sales growth curve would point upward more sharply in 2021, he acknowledged the market power of the on-body injector and indicated that Coherus is working on its own version. He said it would be premature to share an anticipated market entry date.

In a discussion of the company’s biosimilar pipeline of products, Lanfear noted the company is developing versions of ranibizumab and aflibercept, both of which are for treatment of macular degeneration. Their respective originator brands are Lucentis and Eylea. The markets for each of these products are about $3 billion, Lanfear said.

Coherus is also developing a biosimilar to adalimumab (reference, Humira), which he said would likely enter the market in December 2023. The biologic is for treatment of rheumatologic and gastrointestinal disorders. Coherus submitted its biologics license application for FDA approval of its adalimumab biosimilar candidate (CHS-1420) at the end of 2020, and assuming regulatory approval, a 

The adalimumab market is changing, with providers starting to use citrate-free, high-concentration versions of this product, which may complicate marketing plans for Coherus and other biosimilar producers.

According to Lanfear, Humira achieved US sales of $15.9 billion in 2020. AbbVie, the originator company, has employed its exclusivity advantage to impose a steady stream of adalimumab price hikes. Humira prices have climbed 6-fold since 2005, according to Lanfear’s presentation.

“Relentless Humira price hikes and payer expense burden create a pent-up demand for biosimilar alternatives,” he said, predicting a “massive decoupling” ahead that would shift supply contracts to biosimilar manufacturers, once biosimilar versions of adalimumab become available in the United States, in 2023.

In a description of Coherus’ marketing strategy for leveraging greater biosimilar revenues, Lanfear said Coherus would target payers most of all, because they have the greatest control over what biologics are used by the health care community, relative to specialty pharmacies, providers, and patients. “We expect payers to have a significant share of power in selecting products and to drive share away from originators if properly incentivized.”

Coherus also has a bevacizumab biosimilar candidate (reference, Avastin) that it is developing in partnership with Innovent Biologics to submit for regulatory approval in the second half of 2021, Lanfear said. Bevacizumab is for the treatment of various types of cancer, including colorectal, lung, and kidney.

Coherus BioSciences CEO Dennis M. Lanfear discusses the company's biosimilar marketing prospects in 2021.

Coherus CEO Discusses Post–COVID-19 Growth Prospects

On the eve of its February 2021 public offering, Prestige Biopharma, of Singapore, reemphasized its focus on developing biosimilars. Company CEO So-yeon Park stated that Prestige aims to develop and market biosimilars to establish a steady stream of operating capital before moving on to develop other types of drugs.

“Developing new drugs is very profitable but is accompanied by lots of risks,” Park was quoted as 

 by Republic of Korea biopharmaceutical press. “With this in mind, we have decided to focus on developing low-risk biosimilars for the time being.”

Park predicted significant growth for biosimilar companies in the near future based on the number of blockbuster biologic originator drugs that are losing patent protection. The company is developing a trastuzumab biosimilar (HD201), and phase 3 clinical trials have been wrapped up. The company has applied for approval in the European Union and plans to file a biologics license application in the United States.

Prestige also is working to complete phase 3 clinical trials for HD204, a biosimilar for bevacizumab (Avastin), with plans to launch in 2022, according to the Korean press report. In addition, the company has an adalimumab biosimilar in development (PBP1502).

Although biosimilars are central to its early growth strategy, the company is developing a pancreatic cancer antibody drug, PBP1510, a monoclonal antibody that targets pancreatic adenocarcinoma up-regulated factor (PAUF). In June 2020, the FDA granted an orphan drug designation to the first-in-class anti-PAUF drug candidate. Similarly, the European Medicines Agency in October 2020 granted a positive opinion for an orphan drug designation for the agent. Orphan status guarantees a lengthy period of product exclusivity, assuming the drug candidate is approved by regulators.

Innovent Biologics, a Suzhou, China–based company, said it has reached an agreement with PT Etana Biotechnologies Indonesia to comarket Innovent’s bevacizumab biosimilar (Byvasda) in Indonesia.

“We are confident that pairing Etana’s commercial expertise in the local Indonesian market with Byvasda’s clinical profile will further accelerate out mission, benefitting patients globally," said Blake Salisbury, MBA, vice president of Business Development of Innovent, in a 

Byvasda received previous approval from Chinese regulators for the treatment of non–small cell lung cancer, metastatic colorectal cancer, and adult recurrent glioblastoma. In January 2020, Innovent contracted with Coherus BioSciences to commercialize the biosimilar in the United States and Canada, after it obtains regulatory approval in those markets. Innovent has yet to obtain Indonesian regulatory approval for Byvasda.

Biosimilars will be the cornerstone for a leap into biologics development and commercialization, according to the CEO of Prestige Biopharma. Also, Innovent Biologics reaches a marketing agreement. 

Prestige Biopharma Plots Biosimilar Growth Strategy

Results were inconclusive in a study of hypertension and proteinuria in 75 patients treated with bevacizumab reference vs biosimilar products, investigators reported at the ASCO Gastrointestinal Cancers Symposium 2021.

They compared incidence of hypertension and proteinuria in patients treated with various chemotherapy regimens in combination with bevacizumab. Investigators evaluated reference bevacizumab (Avastin) vs 2 biosimilars introduced on the US market starting in 2019: Mvasi, first marketed in July 2019, and Zirabev, first marketed in January 2020. The study period extended from January 2019 to July 2020 and enrolled patients with gastrointestinal cancer at Roswell Park Comprehensive Cancer Center at Buffalo, New York.

“Early recognition of uncontrolled blood pressures and worsening kidney function is needed to prevent delayed intervention,” investigators said, recommending routine monitoring of hypertension and proteinuria following treatment with bevacizumab.

Bevacizumab is a recombinant humanized monoclonal antibody that targets the development of blood vessels that support the growth of tumors. Hypertension and proteinuria, which can lead to pulmonary edema and affects kidney health, are adverse events of bevacizumab.

Investigators noted a higher risk of hypertension in the reference bevacizumab group (52.4% vs 36.4%), although this was not statistically significant (

 = .2427). They observed hypertension in patients after a median of 5 doses of reference bevacizumab vs 1.5 doses of bevacizumab biosimilar (

Investigators observed a higher risk of proteinuria for patients treated with reference bevacizumab vs bevacizumab biosimilar (35.7% vs 30%), although this difference was not statistically significant (

 = .7193). However, proteinuria occurred later in the treatment cycle with reference bevacizumab than with bevacizumab biosimilar (median, 213 days vs 53.5 days following the first bevacizumab dose; 

Investigators concluded that the incidence of hypertension and proteinuria in patients treated with reference vs biosimilar bevacizumab requires study in larger patient cohorts.

Man Y, Yu H, Mukerjee S, Zalewski O. Incidence of hypertension and proteinuria in patients treated with bevacizumab versus bevacizumab biosimilar. Presented at ASCO GI Cancers Symposium 2021; January 15-17, 2021. Accessed January 19, 2021. 

https://meetinglibrary.asco.org/record/194106/abstract

The study was designed to elucidate incidence of hypertension and proteinuria in patients treated with bevacizumab reference vs biosimilar products. 

Investigators Study Risks of Hypertension, Proteinuria With Bevacizumab

Investigators have demonstrated that initial uptake of the first bevacizumab biosimilar (Mvasi, Amgen) in the United States was strongest for patients receiving treatment for metastatic colorectal cancer (mCRC).

 at the ASCO Gastrointestinal Cancers Symposium 2021, investigators sought to evaluate uptake of Mvasi, which was approved by the FDA for all indications of the reference product (Avastin): mCRC, cervical cancer (CC), non–small cell lung cancer (NSCLC), glioblastoma (GBM), and metastatic renal cell carcinoma (mRCC).

They also concluded that, based on the findings, providers were comfortable initiating or transitioning patients to the bevacizumab biosimilar, and they saw little difference in patient characteristics or demographics between those who previously received the reference product and those who initiated treatment with the bevacizumab biosimilar.

The investigators drew patient data from a Flatiron Health electronic health records database,  Oncology Services Comprehensive Electronic Records, which included cancer treatment information for 2.2 million patients from over 280 cancer clinics. The study included patients who received a bevacizumab biosimilar infusion between July 2019, when Mvasi was first approved, and April 2020 (9 months).

The bevacizumab biosimilar was first used in a patient with mCRC, and this occurred within 10 days of product launch. Ultimately, during the study period, 68% of patients with mCRC received an infusion of Mvasi. The other indications accounted for lower biosimilar use: NSCLC, 14%; GBM, 11%; CC, 5%; and mRCC, 1% (

Patients eligible for inclusion numbered 1657, among whom 685 had no prior reference drug treatment vs 972 who did. The investigators said 49% of patients (810) were younger than 65 years, and 60% were White; 11%, Black; and 2%, Asian. The race distribution between those with no prior reference drug and prior reference drug was equivalent, 84% of patients had Eastern Cooperative Oncology Group (ECOG) scores of 0/1, and median body weight was 78 kg. ECOG is a measure of a patient’s ability to function independently, with 0 representing the highest functioning patients and 5 indicating deceased.

The investigators said 59% of patients with mCRC received the reference product prior to receiving the biosimilar. Among other tumor types, the respective percentages ranged from 42% to 50%.

For 67% of patients with mCRC, the average length of time that elapsed between the last reference drug infusion and biosimilar initiation was ≤ 28 days.

A second bevacizumab biosimilar (Zirabev, Pfizer) was launched in the United States in January 2020. Mvasi was 

at a 15% discount to the reference drug wholesale acquisition cost (WAC; $677 vs $797, respectively) and a 12% average sales price discount (ASP; $677 vs $767). Zirabev was launched at 23% and 19% WAC and ASP discounts, respectively ($613 vs $797 and $613 vs $761, respectively). These sales data, provided in a 2020 report from Amgen, reflect the early 2020 launch of Zirabev and the changes in ASP and WAC that occurred since Mvasi was launched in the third quarter of 2019. 

As of the second quarter of 2020, Mvasi had attained a 38% market share in the United States vs 2% for Zirabev.

Jin R, Accortt NA, Sandschafer D, Lawrence T, Loaiza-Bonilla A. Initial experience of patients treated in a real-world clinical setting with bevacizumab-awwb: the first FDA-approved biosimilar to bevacizumab. Presented at: ASCO GI Cancers Symposium; January 15-17, 2021. Accessed January 15, 2021. https://meetinglibrary.asco.org/record/194163/poster

Investigators looked at the first 9 months of use following the launch of the bevacizumab biosimilar Mvasi to gauge physician comfort with this agent across tumor types.

Swift Uptake for Mvasi Suggests Provider Comfort With Use

The International Generic and Biosimilar Medicines Association (IGBA), a trade group with global corporate membership, has appointed a new chair for 2021: Sudarshan Jain, PGDM, secretary general of the Indian Pharmaceutical Alliance. He replaces outgoing IGBA Chair Hanan Sboul.

Jain was described as a veteran of the pharma industry with many years of leadership and drug policy experience. “Increased and sustainable patient access to high quality medicines worldwide, as well as balanaced intellectual property systems remain our key priorities,” he said in a 

“More than ever, we need to transform the lessons learned from the current pandemic and public health crises into resilience of the supply chain of active pharmaceutical ingredients and finished products and ensure that the needs of patients and their access to affordable, safe, and effective generic biosimilar medicines are taken into account in trade agreements,” Jain said.

The IGBA made use of the occasion to tout its achievements in 2020. The group signed an 

with the World Health Organization that the two would partner in easing registration of generics and biosimilars and simplifying the biosimilar approval process.

it conducted jointly with IQVIA to counter arguments that reducing product exclusivity terms would cause a reduction in investment in new and improved medicines. The group claimed to have found numerous examples of how originator product exclusivity protections reduced the savings that would have resulted from generic and biosimilar competition.

for regulatory authorities that offered ideas for improving conditions for a sustained, competitive biosimilar market. These guidelines called for streamlining regulatory policies for biosimilars, with an emphasis on those governing biosimilar development. The group noted improvements in analytical analysis for the support of biosimilar approvals and added its own argument to the weight of opinion forming against the need for comparative clinical efficacy trials of biosimilars, which are often considered redundant and not as useful for regulatory decisions on these agents. 

to promote biosimilars it called Global Biosimilars Week, which was in November 2020.

Celltrion of Incheon, Republic of Korea, has 

an investigational new drug (IND) application with the FDA for its biosimilar candidate referencing denosumab (Prolia), for which there currently are no biosimilars available on the US market. An IND is filed when a company wishes to test a drug candidate in humans. Celltrion aims to launch a phase 3 clinical trial of the denosumab candidate (CT-P41), recruiting 416 patients, and complete the trial by the early half of 2024, according to a Korean press report.

Denosumab is an injectable indicated for the treatment of patients with bone health issues, such as osteoporosis and hypercalcemia. The originator company is Amgen, and denosumab was first 

in June 2010, with an indication for high-fracture risk postmenopausal osteoporosis. Further indications were later added for bone loss in patients with prostate and breast cancer, men with high-fracture-risk osteoporosis, and glucocorticoid-induced osteoporosis.

Amgen reported $2.7 billion in 2010 revenues for the product, vs $2.3 billion in 2018. In third-quarter 2020 results, denosumab 

were up 11% quarter over comparable quarter, indicating continued growth.

There are no denosumab biosimilars available in Europe.

Innovent Biologics, of Suzhou, Jiangsu, China, has announced a string of developments related to its bevacizumab biosimilar, Byvasda. After reporting that the National Medical Products Administration (NMPA) of China 

Byvasda for the treatment of adult recurrent glioblastoma, in late December 2020, Innovent this week stated that the NMPA had 

a supplemental new drug application for the company’s sintilimab injection (Tyvyt) for use in combination with Byvasda as first-line therapy for patients with hepatocellular carcinoma.

Kamada, an Israel-based company with rabies and lung disease products in circulation, has 

 to distribute biosimilars in Israel on behalf of 2 unnamed international biopharmaceutical companies, the company said in a statement.

Kamada has previously signed an agreement with Alvotech of Reykjavik, Iceland, for the Israel-based commercialization of 6 biosimilars still under development. The new agreements involve 3 biosimilar product candidates that Kamada anticipates bringing to market between 2022 and 2024.

In the United States, the company markets the protease inhibitor alpha-1 antitrypsin (Glassia) for the treatment of lung problems caused by an inability to fight off bacteria.

The Center for Biosimilars® reports on developments at the International Generic and Biosimilar Medicines Association (IGBA), Celltrion, Innovent Biologics, and Kamada. 

IGBA, Celltrion, Others Mark Biosimilar Advances

In a move that may reduce burnout for providers and get needed medications, such as biosimilars, into the hands of patients faster and with less hassle, CMS has established a new 

on prior authorizations and the electronic exchange of health information.

The system sets deadlines for payers to approve or deny urgent requests for health care, requires them to provide reasons for their decisions, and incorporates the use of electronic interface applications that facilitate the communication of health records information between providers and payers.

Seema Verma, administrator of CMS, has described the “new rule” as a 

from “Stone Age” reliance on fax machines; a move that gives patients, payers, and providers ready access to patient data; and an end to “mindless nitpicking and wrangling” over patient entitlements to care.

She described the rule as “the result of numerous listening sessions with plans and providers aimed at crafting a new process that balances the need for greater efficiency and consistency in prior authorization with its important role in preventing fraud, abuse, and unnecessary expenditures.”

The new policy was developed by the Office of Burden Reduction and Health Informatics, which CMS created in June 2020 specifically to increase the efficiency of health information transfers and ease regulatory and administrative burdens faced by providers.

CMS also hopes to see a reduction in repeated requests for prior authorization and an overall reduction in health care costs.

The new CMS Interoperability and Prior Authorization rule affects Medicaid and Children’s Health Insurance Program (CHIP) managed care plans, state Medicaid and CHIP fee-for-service programs, and issuers of individual market Qualified Health Plans on the federally facilitated exchanges. These payers would have to implement software to allow the smooth flow of electronic health information about patients and assist with prior authorization.

The deadlines affecting maximum response time for prior authorization requests go into effect on January 1, 2024. For nonurgent requests, payers will have a full calendar week to respond.

“For patients, there will be no more wrangling with prior providers and locating ancient fax machines to take possession of one’s own data; for providers, there will be no more piecing together patient health histories based on incomplete, half-forgotten snippets of information pried out of the patients themselves; for payers, this is the first step towards building the important data sharing systems we need to move towards value,” Verma said.

last year, prior authorizations were cited as a growing burden on physicians, 91% of whom said they believe prior authorization requirements delayed patients’ access to care and 88% of whom said the burden of these requirements has increased in recent years. 

CMS looks to speed up health information transfer by putting faxes in the past. It also aims to set deadlines for payers to respond to prior authorization requests. 

With New Policy, CMS Promises to Exit "Stone Age" of Health Information 

Rapid health care reforms in China have led to a regulatory environment that improves conditions for biosimilar development and approval, according to Lawrence A. Hill, PharmD, MBA, RPh, BCPS. Hill is CEO of Gan & Lee Pharmaceuticals, a company specializing in the development and marketing of insulin products in Asia.

Hill, who spoke at the recent Festival of Biologics virtual meeting, said that biosimilars and China go well together because the country has a large “copy” culture in medicine. The country has 382 biologic drugs and vaccines, and just 21 of those are innovative or originator products, he said.

China has supercharged the growth of its biologics industry with a massive health care reform begun in 2008. In 2003, according to the Chinese Ministry of Health, just 55% of urban residents and 21% of rural residents in China had insurance 

. The reform program boosted coverage to 97% of individuals by 2015; however, according to Hill, many of the most expensive medicines still must be paid out-of-pocket. The difficulty many residents of China have in paying for modern medicine makes this a very price sensitive market, which also improves the potential for biosimilar uptake, owing to their cost advantages, he said.

Biosimilars are considered an “integral part” of China’s effort to achieve universal coverage, with the first biosimilar, for rituximab, approved in February 2019. The country has a population of 1.3 billion and its biologics market was the second largest by sales in 2017. This market is also growing fast, with a 16% compound annual growth rate (CAGR) from 2010 to 2021. The market for copy biologics is growing at a 25% CAGR, Hill said.

As a result of the modernization effort, China’s regulatory system for drugs is rapidly coming to resemble the frameworks that have been established in the United States and European Union, Hill said. Priority review for drugs with exceptional clinical value was established in 2016, followed in 2017 by many guidelines for easing acceptance of imported drugs, conditional approvals of urgently needed drugs, and an “orange book” for generic product standards.

Regulatory enhancements from 2018 cover fast approvals for urgently needed foreign drugs. “Companies that can provide evidence of a drug working equally well across races can immediately apply for marketing approval with existing data and be eligible for priority review,” Hill said. Guidelines for accepting overseas clinical trial data and a shortening of the regulatory review period leading to drug approval also came about in 2018. Companies can even move forward with clinical trials if China’s Center for Drug Evaluation (CDE) does not meet preset deadlines for responding with comments, Hill noted.

In 2015, the CDE published final technical guidance for the development and evaluation of copy biologicals. This established principles for research, development, and evaluation of biosimilars, and it defines a biosimilar along lines almost identical to those accepted in the United States and Europe, namely that the drug must be similar in quality, safety, and efficacy and should have an  amino acid sequence that is identical to the originator product.

There are some key differences. Chinese authorities almost always require a comparative clinical efficacy study for a biosimilar, something that regulators may request in the United States or European Union but which in those regions is increasingly considered of little value compared with other biosimilar development groundwork, such as structural and functional characterization and comparative analytical, nonclinical, and clinical stepwise evaluation.

China will not accept a reference product that has been approved by foreign regulators. By comparison, US regulators may accept a foreign reference product if bridging studies are done to demonstrate biosimilarity. There is no established interchangeability policy in China for the substitution of biosimilars for reference products at the pharmacy counter, and the country has no specific standard for biosimilar naming. In the United States, a system of suffixes is applied to approved biosimilars to aid in drug identification and real-world performance tracking.

“The biosimilar regulatory environment in China has been evolving extremely rapidly,” Hill concluded. This has occurred against a backdrop of “exceptionally aggressive” modernization of the pharmaceutical regulatory environment.

Entering the market is challenging for foreign companies, and Hill said the only route of entry for a foreign concern is to partner with a local biopharmaceutical company that can provide guidance and the sponsorship needed for foreign applications. “There are exceptional commercialization opportunities within China. Foreign products are being welcomed,” he said.

Amgen, of Thousand Oaks, California, is one of the outside companies that has taken the 

 of local sponsorship. In 2017, the company partnered with Simcere of Nanjing, China, to codevelop and distribute biosimilars in China for patients with cancer and inflammatory diseases. And in 2019, Samsung Bioepis, of Incheon, Republic of Korea, 

 with the Chinese biopharmaceutical company 3SBio to develop and commercialize biosimilars, including SB8, a bevacizumab biosimilar referencing Avastin.

Some Chinese companies are becoming biosimilar pioneers in their own right. These include Henlius, Innovent, Bio-Thera, and Hisun Pharmaceuticals. Henlius obtained the first biosimilar approval in China and has a large pipeline of products. The company most recently reported Chinese regulatory acceptance for HLX03, an 

 biosimilar for the treatment of rheumatoid arthritis, ankylosing spondylitis, and plaque psoriasis. This marks the third biosimilar approval in China for Henlius.

Hill’s company, Gan & Lee, was founded as Beijing Gan & Lee Biotechnology and developed the first recombinant human insulin (Gansulin) in China.

Lawrence A. Hill, PharmD, MBA, RPH, BCPS, provided an insider's view of the rapidly changing biologics and biosimilars market and regulatory structure in China. 

Hill Describes Supercharged Biologics Market in China

Investigators have reported pharmacokinetic (PK) findings that confirm the biosimilarity of Viatris’ trastuzumab biosimilar candidate (MYL-14010, Ogivri) to reference Herceptin. Ogivri, developed by Mylan, which is now Viatris, was approved by the FDA in 2017.

 randomized phase 3 study, which previously demonstrated comparable efficacy and safety for Ogivri vs Herceptin as frontline treatment for women with human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. The biosimilar was launched in the United States in December 2019, and these latest findings were presented at the 2020 San Antonio Breast Cancer Symposium (SABCS).

Patients (N = 485) were randomized to receive the biosimilar (n = 245) or reference product (n = 240) in combination with a taxane (docetaxel or paclitaxel) every 3 weeks for 24 weeks for 8 cycles, followed by additional cycles of monotherapy until disease progression, discontinuation, or unacceptable toxicity.

Primary objectives of the study were to compare drug concentration variation (area under the curve), maximum serum drug concentration, clearance (drug elimination), drug propensity to leave the plasma (volume of distribution), and terminal elimination half-life (no further drug distribution or absorption).

The investigators also sought to assess shed extracellular domain (ECD) HER2 receptor fragments and their effect on PK parameters. The decrease of shed ECD HER2 fragments is associated with an improved prognosis in metastatic breast cancer.

They took PK samples from patients at cycles 1, 2, 4, 6, 8, and 9 (monotherapy) to assess minimum serum concentrations. Serum maximum concentration samples were collected at the end of cycles 1 and 6. Additional samples were collected from a population subset. The final analysis included 213 patients in the biosimilar group and 202 in the Herceptin group.

No notable differences in demographics were observed between the 2 patient cohorts, the investigators said, noting there were no dissimilarities in trastuzumab concentrations between the groups. Treatment (biosimilar or reference) was not a significant covariate of clearance (

However, ECD HER2 concentration was a significant factor in trastuzumab clearance, and weight was also a significant covariate of clearance and drug distribution (volume of the central compartment).

In the trough concentration (lowest drug concentration before the next dose) analysis, data were comparable between treatment arms at the end of cycles 1 and 6, the investigators said (

They used Bayesian statistics to evaluate steady state drug exposure between treatment arms and found comparable results indicating PK biosimilarity between the biosimilar and reference drugs. Steady state represents equivalent rates of drug absorption and elimination.

A low frequency of antidrug antibodies, which counteracts the effects of trastuzumab, were observed between Ogivri (n = 14) and Herceptin (n = 21).

Investigators concluded the population PK profiles of Ogivri vs Herceptin were comparable in patients with HER2-positive metastatic breast cancer. They said the study confirmed earlier PK findings.

Financial support for the study and its presentation at SABCS was provided by Viatris, investigators said.

Owen J, Rackley R, Liu M, et al. Population pharmacokinetics of MYL-14010 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2-positvie metastatic breast cancer. Poster presented at: SABCS; December 8-11, 2020. PS18-23. https://sabcs.onlineeventpro.freeman.com/single-file-viewer/25581567

Pharmacokinetic (PK) parameters matched up with those of reference trastuzumab in an extended analysis of data from the HERITAGE trial. 

Data From HERITAGE Confirm PK Biosimilarity for Ogivri

Biosimilar policy should aim to lower costs of care, as increasing biosimilar uptake is not necessarily a direct route to savings, argue the authors of an 

 of the health economics of this rising class of agents. Multiple factors go into whether biosimilars improve access to care, but ultimately their success can best be measured by cost reduction, they wrote.

“We believe that biopharmaceutical policy should aim to create a competitive and sustainable market for off-patent reference biologics, biosimilars, and next-generation biologics with a view to making biologic therapy available to patients at the lowest cost, rather than to promote biosimilar uptake. This serves to maximize savings,” they wrote.

Their study was a scoping review of available literature on biosimilar health economics, which they said is a subject that has not been sufficiently addressed and requires more investigation. They focused mainly on the use of biosimilars and the consequent savings in the European Union, because biosimilars are more established there than in the United States.

The authors concluded that biosimilar competition in the drug marketplace contributes to lower costs of health care, although that measure alone cannot provide a true picture of whether biosimilars are having the desired effect on cost and access to care. Further, they said, competition from biosimilars provides pharmaceutical companies with the initiative to develop new biologics that raise the quality and efficacy of care.

“Manufacturers may safeguard their economic viability by focusing on the development of new biologic therapies for which there is no biosimilar competition, as long as patents and exclusivities have not expired," the authors stated. This was the case for AbbVie, which moved on to the development of Janus kinase inhibitors as its adalimumab blockbuster medicine (Humira) moved closer to patent expiration, they wrote.

But not enough is known about how biosimilars affect drug competition and innovation once they enter the marketplace. The authors cited one study that suggested that genuine competition among rival brands begins when there are at least 2 biosimilars in the market for a single drug type.

Based on their analysis, they asserted that “the relevant outcome measure is the evolution in the average cost of biologic therapy over time instead of biosimilar market share.” The Netherlands achieved a 44% and 50% net reduction in per-patient hospital expenditure for etanercept and infliximab, respectively, between 2014 and 2018, and these results clearly indicate a successful biosimilar policy, they wrote. Although not the sole determinant for biosimilar cost savings, market share still is an important element of a competitive market for biologics, they said.

Lower-priced biosimilars can have a downward effect on the price of reference biologics through price competition among manufacturers, and a 5-year study in Italy of the market entry of rituximab biosimilars demonstrated that price competition accounted for 67% of savings achieved.

Some countries in Europe have placed less reliance on price competition and more on price regulation. In Spain, for instance, reference biologic prices must drop to the level of biosimilar prices, “although price competition can lead to further price reductions,” the authors wrote.

They included an evaluation of “tenders,” which in Europe are systems of awarding contracts to a single, at most a few, biosimilar manufacturers/providers. This causes initial competition among producers to win the tenders, but in cases where only 1 biosimilar wins the tender, there is a risk that other producers will lose interest in competing in future tender opportunities. This is an oft-cited criticism of the tender process.

"Multiple-winner tenders may generate the largest savings because they attain price decreases on all tendered products for all use indications,” the authors said, citing available evidence.

How the savings from cost reductions are employed is interesting, the authors wrote. A study in the United Kingdom evaluated whether more health gain resulted from using biosimilar adalimumab savings to treat patients with rheumatoid arthritis (an adalimumab indication) or patients with melanoma, hepatitis C, multiple sclerosis, Duchenne muscular dystrophy, or non–small cell lung cancer. The authors noted that the greatest cost-effectiveness resulted when those savings were spent on treating patients with hepatitis C.

The authors said little information is available on whether nonmedical switching from reference to biosimilar products results in savings. However, in Scotland, the National Health Service is attempting to achieve savings through nonmedical switching, they said.

When trying to determine the true budget impact of biosimilar use, it’s important to consider such dynamics as evolution of the epidemiology of the disease, initiation of biologic-naïve patients on a biosimilar and switching practices, price competition with alternative therapies, and the effect of innovative new drugs. The authors said few budget-impact analyses have looked at biosimilar savings from such a wide perspective.

Narrowing it down to just reference vs biosimilar drugs, it is possible to achieve a picture of cost-effectiveness, they said. For example, a Canadian spending analysis looked at reference vs biosimilar cetuximab plus best supportive care in a population with metastatic colon cancer. The authors said the incremental cost-effectiveness ratio was $299,613 vs $261,126 per quality-adjusted life year for reference vs biosimilar cetuximab, respectively.

“The cost-effectiveness of biologic therapy can change through its lifecycle as a result of, for example, the market entry of biosimilars or of new innovative chemical or biologic medicines,” the authors said. They added that payer policies and rebates play a critical role in how much savings is achieved with biosimilars.

Further, competition introduced to the market via the arrival of second-generation biologics with different administration routes than first-generation biologics can influence the cost savings. “The administration form has implications,” they said. Important variables to consider include the health care setting in which the biologic is used (hospital vs home), biologic use in combination with chemotherapy, and type of dosing regimen (body-weighted adjusted dose vs fixed dose). Even a manufacturer’s value-added services, such as patient support, factor into the cost-effectiveness equation.

Simoens S, Vulto AG. A health economic guide to market access of biosimilars. 

. Published online November 18, 2020. doi:10.1080/14712598.2021.1849132

Authors of a review found that biosimilar uptake and market share are not in themselves sufficient to establish whether these agents will lead to savings.