Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

German biotechnology company Fresenius Kabi said the European Medicines Agency (EMA) has accepted its marketing application for the pegfilgrastim biosimilar MSB11455, a version of Amgen’s Neulasta.

The EMA’s decision to review the application marks a new milestone for Fresenius Kabi, which last year gained EMA approval for an adalimumab biosimilar, Idacio, and launched it on the European market.

“This is an important achievement in the development of our entire biosimilar pipeline and oncology portfolio,” said Michael Schönhofen, a member of the Fresenius Kabi management board and president of its Pharmaceuticals and Devices Division, in a 

MSB11455 stimulates the growth of white blood cells that are essential to fight infections, a common adverse event in patients receiving chemotherapy for cancer. MSB11455 was developed in Switzerland by Fresenius Kabi’s immunology and oncology research lab there.

The EMA Marketing Authorization Application submission for the pegfilgrastim biosimilar candidate includes analytical, pharmacokinetic, pharmacodynamic, safety and immunogenicity data. Two pivotal clinical trials were conducted that showed the drug had an equivalent pharmacokinetic and pharmacodynamic profile to reference pegfilgrastim, as well as similar immunogenicity, in healthy volunteers. Company officials said the product’s safety profile also was comparable to pegfilgrastim.

Pegfilgrastim is a long-acting form of filgrastim, a recombinant human granulocyte colony-stimulating factor, or G-CSF, that stimulates the production of neutrophils, or white blood cells. The reference product is approved in the European Union for reducing the duration of neutropenia and the incidence of febrile neutropenia in adult patients.

, Fresenius Kabi noted its pegfilgrastim candidate demonstrated safety and immunogenicity similarity to the reference product. Pharmacokinetic and pharmacodynamic equivalence were previously demonstrated for this agent.

Fresenius Kabi also is developing a tocilizumab biosimilar, for rheumatoid arthritis.

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On the heels of positive clinical studies, Fresenius Kabi said the European Medicines Agency will review its product application for a pegfilgrastim biosimilar.
 

Amgen May Face New Pegfilgrastim Biosimilar

Biosimilars have potential to bring down costs and they may not be used as often as they should be, particularly because they are carefully patterned after innovator drugs that command higher prices, but among payers and health plans, the discussion whether to incentivize the use of these products remains “ongoing,” said Bhuvana Sagar, MD, national medical executive for Cigna Health Care, a panelist who spoke during the National Comprehensive Cancer Network (NCCN) 2020 Virtual Annual Conference.

“It’s still very difficult to incentivize optimal use, although I’m sure a lot of payers are looking at this very issue of how to promote the utilization of drugs that are essentially safe and lower-cost options,” Sagar said.

Panelists discussed the sensitive issue of rebates as incentives for biosimilar uptake, as well as related issues connected with the use of these agents. Rebates may incentivize use of a particular drug, but not always for the right reasons, said panelist Michael Kolodziej, MD, a vice president and chief innovation officer for ADVI Health.

Rebates and the Medicare Modernization Act

Prior to the Medicare Modernization Act of 2003, rebates were primarily agreements between manufacturers and provider organizations to bring down the price of a drug based on the degree of utilization, Kolodziej said. This led to an increase in the margin that providers could earn by prescribing that particular drug in quantity.

The Medicare Modernization Act introduced the concept of average sales price (ASP), which is the net cost of a medicine after all discounts have been subtracted, and this is the amount that Medicare bases its payments on. “So, theoretically, in an ASP-based world, rebates shouldn’t exist,” Kolodziej said.

However, they do. Manufacturers can still incentivize use of their products through rebates because ASP prices are not updated for months after sales actually occur, and so a manufacturer can reduce cost for a provider organization through a rebate and those providers can still gain a margin of revenue that would not exist in a real-time ASP world, Kolodziej said. “These rebates are invariably tied to preferred formulary position. You have to agree to use a certain amount of a drug in a given category.”

“This is adult talk,” Kolodziej added. “This is the way the world works.”

In a new twist to the rebate deal, “the payers have decided that they would like some of that rebate money, and they are negotiating directly with the biosimilar manufacturer or the reference product manufacturer to get a discount so that they have a lower net.…Now, the payers are in on it, and there’s direct conflict, and that’s why this has gotten to be such a sensitive issue,” he said.

The rebate dynamic creates trickle-down problems, noted panelist Scott A. Soefje, PharmD, RPh, director of the Department of Pharmacy at Mayo Clinic. One of those issues is complexity and making sure that health care is executed safely and efficiently.

He noted that there are 6 trastuzumab products, including reference and biosimilar drugs, and so there are multiple commercial entities angling to get those agents, all essentially the same type of product, into the clinic. “Imagine a world where we have 6 different payers in each region who negotiated 6 different contracts for rebates, and each one is demanding different trastuzumabs.

“In our pharmacies, that means we have to stock all of them,” Soefje said. “We have to make sure we’re pulling the right drug out of the refrigerator to give it to the patient. So now you have sound-alike, look-alike boxes.” It has the potential to confuse clinicians and pharmacists. The provider institution has “no contracting power whatsoever” and cannot, for example, reduce the number of trastuzumabs to avoid this scenario and make things easier for health care workers and safer for patients, Soefje said.

The pharmacy acrobatics required to skillfully manage multiple versions of an identical product run counter to the actual need for a single biosimilar product that would vastly improve conditions, said panelist Drew S. Mace, PharmD, pharmacy supervisor at the Ann B. Barshinger Cancer Institute in Lancaster, Pennsylvania.

With respect to biosimilars and reference products, “by and large, we have noticed zero difference in terms of efficacy and/or safety when we have performed our pharmacovigilance,” Mace said. This pharmacovigilance at his institution has been considered necessary to quell any lingering concerns that prescribers may have with biosimilars. “We would view any biosimilar equivalent in terms of interchangeability.”

 reported the NCCN panelists’ discussion about patient education on biosimilars.

Drug rebates have survived despite the payment reforms imposed by the Medicare Modernization Act of 2003, and now payers are taking advantage of them, too, panelists noted at the National Comprehensive Cancer Network (NCCN) 2020 Virtual Annual Conference.

Part II: NCCN Panelists Take On Drug Rebates

Switching patients to biosimilars can sometimes be a difficult feat, given patient preferences, which may be determined only by what a patient may have heard about a biosimilar from an acquaintance, panelists said in a biosimilars discussion, “Role of Biosimilars in the Oncology Ecosystem,” at the National Comprehensive Cancer Network (NCCN) Virtual 2020 Annual Conference, May 15, 2020.

“We’ve seen a handful of patients who have outright refused conversion to a therapeutic biosimilar because of rumors or perceptions by other patients who have experience or have used the biosimiliar and have had worse adverse events in their opinion, or have not had a great experience,” said Drew S. Mace, PharmD, pharmacy supervisor at the Ann B. Barshinger Cancer Institute in Lancaster, Pennsylvania.

Studies have demonstrated strong patient concerns about 

. “That’s the patient conundrum that we’re trying to deal with, but ultimately, it is their decision, even as financially toxic as it may be for them. Some folks really don’t mind,” he said.

However, the advantage of a biosimilar is that it is a therapy that is therapeutically equivalent to an original drug and often offers the prospect of significant savings, panelists said. Further, a decade of experience with biosimilars in Europe suggests that there are no significant safety or efficacy concerns that ought to dissuade patients from choosing these agents, said Scott A. Soefje, PharmD, RPh, director of the Department of Pharmacy at Mayo Clinic in Rochester, Minnesota.

In incorporating biosimilars into its therapeutic plans, Mayo had to escape from the gravitational pull of innovator companies, who wanted the clinic to continue using its brands for their patients. “We had no incentive to switch away from them,” Soefje said.

That began to change as payers started demanding that biosimilars be used. “We’re happy that payers are coming back and saying we don’t care which biosimilar you use, just use a biosimilar.” Mayo has adjusted its electronic medical record system to give pharmacists more power to move preferred biosimilars into treatment regimens.

The experience at Barshinger has been similar, Mace said. Treatment plans have been “defaulted” to biosimilar agents. For patients who are initiating therapy, there’s really no reason for the provider to be heavily involved in the prescription choice of biosimilar over reference product. That said, “It becomes very complex when converting someone who was established on a reference product to a biosimilar. There’s a lot of education that needs to occur on the front end, both with the prescriber as well as the patient,” Mace said.

Patients often develop their own preferences for drugs from their participation in blogs and support groups, “so, unfortunately, as great as they are for all the social help that they provide for someone who’s undergoing cancer care, sometimes they’re an area where rumors or disinformation can actually spread,” he said.

The education component is difficult, as is managing the fears and concerns that patients have regarding converting from a reference product to a biosimilar, he said. Patients worry that “This is different. Its name is different, and therefore it must be a different or even an inferior drug.”  

When it comes to patient conversions to biosimilars, Mayo doesn’t flatly refuse to allow the patient any choice, Soefje said. Patients can say no, that they don’t want the conversion, but if their payer happens to be demanding a biosimilar, the clinic has to be upfront with them and warn them that going with a reference product is going to result in additional cost.

Soefje said Mayo does try to put a limit on the number of switches within the spectrum of available reference and biosimilar products. “We won’t allow more than a single switch.”

Patient preferences play a large role in the effort to get biosimilars into the mainstream of therapeutics, and education is often a struggle, panelists said at the National Comprehensive Cancer Network (NCCN) 2020 Virtual Annual Conference.

Part 1: NCCN Panel Discusses Patient Education on Biosimilars

Biosimilars are gaining traction in the United states, but the majority of payers are putting them on an equal footing with reference drugs when it comes to coverage decisions, 

US health plans granted preferred status to biosimilars in just 14% of coverage decisions, according to a survey of decisions issued by 17 of the largest US commercial health plans, representing approximately 60% of commercially covered patients. By contrast, the reference product was given preferred status in 33% of decisions, and in 53% of decisions, neither the biosimilar nor the reference product was preferred.

The study was conducted by investigators from the Center for the Evaluation of Value and Risk in Health at Tufts Medical Center in Boston, Massachusetts. They evaluated 535 coverage decisions for biosimilars available in the United States in August 2019.

Investigators treated a biosimilar brand and an indication for that biosimilar as an individual coverage decision. For example, there were 5 potential coverage decisions a payer could make for Mvasi, a bevacizumab biosimilar indicated for 5 types of cancer.

There was variation in how payers covered biosimilars. Just 2 of the plans covered biosimilars as preferred products in ≥ 50% of their decisions. Two health plans always covered biosimilars and reference products with no preferences in each decision.

There was also variation in decisions regarding types of biosimilars. For example, 51% of plans gave the Zarxio filgrastim biosimilar preferred status, but 65% and 59% of plans preferred the reference product over the Renflexis and Inflectra infliximab biosimilars, respectively.

“Reasons for this variation are unknown, but may include more successful negotiation of rebates at some plans than others,” the authors wrote. They said rebates are not publicly disclosed, which makes it difficult to verify this hypothesis.

The authors concluded that their findings may help to further elucidate why uptake of biosimilars may be lagging in the United States.

“The slow uptake of biosimilars in the US has been attributed to factors such as patent disputes and reference product manufacturer tactics to delay biosimilar market entry. This study suggests that a lack of preferred coverage among health plans may also be delaying uptake,” they wrote.

Earlier this year, Health New England said that it had

over a year's span by using prior authorization to spur use of biosimilar infliximab, achieving 93% utilization.

Chambers JD, Lai RC, Margaretos NM, Panzer AD, Cohen JT, Neumann PJ. Coverage for biosimilars vs reference products among US commercial health plans. 

 2020;19;323(19):1972-1973. doi:10.1001/jama.2020.2229

A study of coverage decisions by some of the nation’s largest payers indicates biosimilars get preferred status just 14% of the time.

Tufts Study: Most Payers Don't Give Preference to Biosimilars

Use of biosimilar forms of filgrastim and pegfilgrastim, both granulocyte-colony stimulating factor (G-CSF) agents, continues to increase over time, although the number of patients using both the reference and biosimilar versions has remained constant, according to a study presented at the National Comprehensive Cancer Network 2020 Virtual Annual Conference.

The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), a nonprofit initiative convened in 2015 under auspices of the Academy of Managed Care Pharmacy (AMCP), evaluated data for 38 million patients covered by commercial or Medicare-Advantage health insurance. The data were derived from a distributed research network (DRN) that includes medical and pharmacy claims data on patients from multiple research partners.

The study presented at the NCCN meeting was designed to help inform future priorities for the BBCIC, and investigators concluded that there is sufficient utilization of biosimilar G-CSFs to support a comparative safety and effectiveness study using the BBCIC DRN.

G-CSF products are used after chemotherapy to help patients’ white blood cell counts recover. Biosimilar G-CSF products began to appear on the US market in 2015. Three filgrastim products and 2 pegfilgrastims were included in the analysis; these included the reference products.

Data were analyzed for “new,” or incident, users, who were defined as not having had G-CSF treatment in the 183 days prior to the episode included in the study: 31,023 filgrastim reference (Neopogen), 5325 tbo-filgrastim (Granix), 6305 filgrastim-sndz (Zarxio), 82,671 pegfilgrastim reference (Neulasta), and 192 pegfilgrastim-jmdb (Fulphilia) incident users were identified. Granix is approved as a biologic in the United States and as a biosimilar in Europe.

Because of the relatively short 183-day interval, it was possible for a single patient to have more than 1 episode of use included in the study.

Other biosimilar versions of filgrastim and pegfilgrastim have been approved more recently than these other agents and could not be included in the study.

Reference filgrastim users numbered over 6000 in 2014 but declined to around 2000 by 2018; use of filgrastim-sndz climbed from 0 users in 2015 to roughly 2000 by 2018; and tbo-filgrastim users climbed from 0 to around 1000 between 2014 and 2018.

Of incident filgrastim-sndz users, 9.5% had a recorded history of filgrastim use and 17.1% had a history of pegfilgrastim use. Of filgrastim users, 1.0% had prior use of filgrastim-sndz and 20.4% had prior use of pegfilgrastim. “This suggests some switching between products occurred,” investigators said.

From 2013 to 2018, reference filgrastim use dropped from a 100.0% share to 37.4%. From 2016, to 2018, the share ascribed to filgrastim-sndz climbed from 21.7% to 43.9%, and from 2014 to 2018, the share attributed to tbo-filgrastim changed from 9.4% to 18.8%.

Use of pegfilgrastim relative to filgrastim remained relatively constant: roughly 66% versus 34%, respectively.

Lockhart CM, McDermott CL, Marshall J, et al. Longitudinal evaluation of characteristics, treatment patterns, and general outcomes among patients using granulocyte colony stimulating factors: a Biologics and Biosimilars Collective Intelligence Consortium study. Poster presented at: National Comprehensive Cancer Network 2020 Virtual Annual Conference; March-May, 2020. nccn.org/professionals/meetings/2020/posters.aspx

A study of filgrastim and pegfilgrastim biosimilars demonstrated data are sufficiently large to support an investigation on the effectiveness of these agents.
 

NCCN Study Lends Support for Safety and Efficacy Investigation 

On July 1, 2020, Canada will tighten up its regulations for the pricing of patented drugs with a series of changes that, among other things, drop 2 countries with among the highest drug prices, the United States and Switzerland, from the list of those whose drug prices can be used as comparators.

Canada will also allow the country’s Patented Medicines Prices Review Board to incorporate 3 new 

into drug pricing decisions: pharmacoeconomic value, market size, and gross domestic product (GDP) in Canada. These will allow the country to weigh the price of a medicine in relation to how it affects the health care system and its value to patients, proponents say.

In a discussion at Virtual ISPOR 2020, the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research, panelists reflected on these changes and other efforts to improve access and affordability to drugs for Canadian residents.

Like the United States, Canada is grappling with the seemingly inexorable rise of drug prices, largely the result of a steady procession of new specialty medicines for which there may not be comparable medicines available at lower cost. In addition to unsustainable prices, drugs are being approved with lower levels of evidence, creating uncertainty about their value across the spectrum of payers, patients, and clinicians, ISPOR panelists said.

“Gene and cell therapies, immunotherapies, and other cancer drugs, and even expensive drugs now used to treat more common diseases are just some of the new blockbusters that are promising to improve health outcomes, but they’re also contributing to the affordability crisis that we’re experiencing,” said Mitch Moneo, moderator and a member of the Therapeutics Initiative Oversight Committee in British Columbia.

The pending regulatory changes have given rise to concerns that drug innovation will be stifled and manufacturers may not want to launch in Canada. This is not the case, said Tanya Potashnik, MA, director of the Policy & Economic Analysis Branch of the Patented Medicines Price Review Board.

“We’ve been looking at this issue quite extensively, and we have provided evidence that, in fact, there are many countries that have lower prices than Canada, but yet outperform Canada with respect to the number of substances that are launched in those countries,” she said.

According to an analysis by her office, “price in and of itself is a weak determinant of whether a manufacturer decides to launch in a country.” Market size, the wealth of a country, and how much is spent on drugs are stronger determinants, she said.

Efforts were also made to find out whether the pre-announcement of these regulatory changes had produced any effect on product launches or the number of clinical trials in the country, and again the answer was negative, Potashnik said. “We’re not seeing any evidence that there have been any negative implications.”

But that doesn’t rule out a follow-up analysis, which will be carried out, she said. “The next focus will be to make sure that we have an evaluation that allows for a comprehensive assessment of the impact of these changes on various aspects of the Canadian ecosystem.”

Other countries also are starting to use pharmacoeconomic value, market size, and GDP to weigh the prices of new drugs in terms of value and affordability, she said.

“When you look at expensive drugs for rare diseases, it is a group of drugs that has been growing at a compounded annual average rate of about 30% over the last 5 years and now accounts for close to 10% of overall sales. So, Canada, like other countries, is finding ways to assess what would be an appropriate price tag for these,” Potashnik said.

A perspective on new drugs and pricing in Canada also was provided by Brent Fraser, BSc, MBA, vice president of Pharmaceutical Reviews for the Canadian Agency for Drugs and Technologies in Health (CADTH), which among other things provides recommendations on coverage for payers.

“The pipelines that we’re seeing with the new drugs coming forward are very robust. This does have some challenges—the fact that the volume of submissions that we’re receiving from manufacturers has been increasing year over year,” he said.

“There is a significant demand to get access to medications earlier,” he added.

Health Canada, an agency within the Canadian government that sets health policy, “is approving some drugs faster than what we’ve seen in the past and often misses on more immature-type data, and as a result it makes the health technology assessment work a bit more challenging.”

There is also a medicine affordability crisis in Canada that is forcing CADTH to move beyond health technology assessments to an intervention role. “We trying to identify those technologies that are most disruptive and for which there is the greatest need for access, and hopefully we can do some work during the regulatory phase so that there isn’t a delay in the recommendations” concerning these agents.

Fraser said CADTH is also talking more to physicians and patients to gauge the need for newer drugs and assess their potential to help patients better than existing medicines. “We're also looking at developing more evidence-informed implementation advice for the payers,” he said.

In July 2020 Canada will implement a series of reforms to help bring runaway drug prices under control, panelists said at Virtual ISPOR 2020, the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research.
 

Canada Grapples With Drug Price Escalation

Alternative payment models (APMs) have long been an experiment in the health care community for incentivizing better, cost-effective care that maintains or improves outcomes, but are they working? This question was addressed by panelists during the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) annual meeting, Virtual ISPOR 2020, held this week.

APMs have notched some successes, said Elizabeth Oyekan, PharmD, a senior executive at Precision Value & Health in Centennial, Colorado. There have been cost savings and improvements in care, but APMs also are connected with higher spending and have been strongly resisted, “especially when it comes to arrangements that require [providers] to assume financial risk,” Oyekan said.

Even so, it is clear that APMs have outperformed strict fee-for-service (FFS) payment systems on many performance and quality measures over time, including in diabetes care, preventative services, and hospital admissions, she said. APMs are models that include payments to incentivize lower-cost, high quality care. Accountable Care Organizations (ACOs), groups of medical providers that may operate under an APM model, have achieved similar results.

"APMs and ACOs have benefited financially from these improved quality measures,” Oyekan said. “And what we’ve seen is increased [patient] enrollment in addition to the financial benefit.” Those with 4 or more stars in the Medicare Advantage Star Rating System have seen a 13.1% increase in enrollment, she noted. “For those that have the coveted 5 stars rating, we have seen that they now have year-round enrollment, which is of extreme benefit to many organizations.”

An additional benefit is that the administrative burden has been lessened through fewer quality measure requirements.

The patient “experience” with health care systems has not deteriorated during the switch from FFS to APMs or ACOs, Oyekan said. “There was the fear that there was going to be some major impact, and that has not happened at this point.”

Some CEOs have been able to reduce costs of care by trimming overutilization of services or therapy and by focusing on higher-value therapies, she said. “And also, the bonus payments [available to APMs and ACOs] have become a new source of revenue for these entities.”

However, in many cases APMs and ACOs create incentives to reduce spending without appropriate quality protections built into them, and for many APMs in the commercial sector, only minor care quality improvements have been achieved. The Medicare Shared Savings program, which governs 517 ACOs, has seen increased Medicare spending, causing concern for CMS, Oyekan said.

“We’ve heard from many providers, and for many the question is, considering the significant behavioral and practice changes that have to occur and the investments it takes to become an APM, is it really worth it? And for many, with regard to the payments they have seen and the bonuses, they’re not quite sure that the change is worth what is being incentivized at this time,” she said.

The bottom line is that although the APM may not be the “final answer” for achieving value-based care, it has provided a good initial framework for grappling with improvements in value of care, she said.

The panel included Anupam B. Jena, MD, PhD, the Ruth L. Newhouse Associate Professor of Health Care Policy at Harvard Medical School in Boston, Massachusetts. With respect to the scale of APM involvement in health care, more than $3 of every $5 is linked to APMs, Jena said.

Some APMs may include elements of FFS spending and bundled care, in which a single payment is received for a suite of services associated with a single clinical episode.

The FFS APM has been a focus of concern "in terms of whether or not it's actually reduced readmissions or whether it's an unintended byproduct of increasing mortality. There are selection cnocerns as well in terms of the types of patients who get hospitalized as a result of the program and the incentives that it places. Nonetheless, I think that this program has been very impactful," Jena said.

A key attribute of these models, Jena said, is that the quality of data and the ability to measure results are much greater now than 20 or 25 years ago.

Further, patient satisfaction is now a metric with many APMs. Patient satisfaction drives patients to a health care center, Jena noted. "The interplay between treatment effectiveness and patient satisfaction is going to be quite relevant, more relevant, I think, with APMs."

Ultimately, for the success of APMs, there has to be accountability, said Michael Barr, MD, MBA, MACP, executive vice president of the National Committee for Quality Assurance in Washington, DC. However, it’s important to clearly define the patient population for which the health care entity will be held accountable, and then performance data must be supplied regularly to guide care decisions, and these data should be acted upon.

Too much data or data for the sake of data can make inefficient workflows more inefficient, he said. “Let’s work on making data efficient and not expect or require any diversion to check a box if any question is not directly related to the delivery of care.”

Similarly, outcome measures should be chosen with care. “No APM will work unless the measures matter. The best way to undermine an accountability model is to select and highlight measures that are not perceived by clinicians in their teams or patients to some degree to be relevant.” Measures should be logical, feasible, usable, manageable, timely and actionable, he said.

Quality measures have evolved, he said. Paper-based measures include claims information, chart extractions, and patient surveys. The next wave was electronic. Electronic health records provided a better way of organizing data. From there, digital quality measures (DQM) emerged.

“This could be our future if we start working together, “Barr said of DQM.  Patient data could be aggregated from multiple providers and organized by compatible systems linked to decision support. Treatment planning could be updated when guidelines change or new therapeutics are introduced, much the same way smartphone applications are updated. “This is the future, now,” Barr said.

Visit The Center for Biosimilars' conference page for more from 

The alternative payment model (APM) doesn’t perfectly balance the competing interests of revenue growth and value-based care, but it has been a learning tool, panelists said at Virtual ISPOR 2020, the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research.
 

ISPOR Panelists Weigh the Success of APMs

Hsinchu, Taiwan—based JHL Biotech said it has initiated a phase 1 clinical trial of its denosumab biosimilar candidate JHL 1266, having randomized and treated the first group of patients.

JHL 1266 is a monoclonal antibody targeting RANKL, a gene that regulates cell death. Denosumab inhibits the development of osteoclasts, which break down bone tissue and release the minerals into the blood stream. The drug thereby prevents breakdown of bones in the human body.

Denosumab is used for the treatment of osteoporosis and hypercalcemia, or above-normal calcium levels. In the United States it is indicated for osteoporosis and improving bone mass in individuals at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer.

The company said the 3-arm study is being conducted in Australia and will compare the pharmacokinetic similarity of JHL 1266 with that of the reference product, Prolia, in healthy patients. The company described the study as pivotal for regulatory approval.

“Denosumab is an important biologic for the treatment of post-menopausal osteoporosis and other common bone related diseases. Because it’s unfortunately very expensive for patients and healthcare payers, JHL1266 would provide an affordable treatment for these patients,” said James Huang, CEO of JHL Biotech, in a 

Taiwan-based JHL Biotech said it has initiated a phase 1 clinical trial of its denosumab biosimilar candidate for bone loss.

JHL Biotech Doses First Patients in Denosumab Trial

Bangalore, India-based Biocon said its subsidiary Biocon Biologics India has received European Union Good Manufacturing Practice (GMP) certification for multiple biosimilars manufacturing facilities in Bengaluru, India.

The certificate of GMP compliance from the European Medicines Agency is for multiple biologics drug substance (DS) and drug product (DP) manufacturing facilities at Biocon Park in Bengaluru.

Biocon is a rising star among Indian biopharmaceutical companies, having successfully launched its products on international markets, a feat that required the company to meet higher standards for manufacturing quality and evidence than are generally required for domestic distribution.

Multiple Biosimilars to Roll off the Conveyor

The company said the Bengaluru facilities are used for the manufacture of DS and DP for bevacizumab, trastuzumab, pegfilgrastim biosimilars, as well as for packaging of insulin glargine for European Union markets. The inspections occurred in March 2020.

Biocon said the approval allows a “multifold” expansion of the company’s capacity to provide trastuzumab and pegfilgrastim for patients in the European markets. The trastuzumab biosimilar was commercialized in March 2019 and the commercialization of a pegfilgrastim product in the European Union is “imminent,” Biocon said in a 

“This certification would further enable the approval process of our biosimilar bevacizumab, the marketing authorization for which is currently under review by the European authorities,” Biocon said.

Christiane Hamacher, CEO and managing director of Biocon Biologics India, said the GMP certification would support the company’s designs to achieve a “milestone of $1 billion in revenues” by fiscal year 2022.

Two Biocon manufacturing facilities in Bengaluru received FDA approval in late 2019, allowing the start of commercial activities there.

The company has partnered with Mylan to commercialize 2 co-developed biosimilars, trastuzumab and insulin glargine, in the European Union.  

In April, Biocon and Mylan launched a pegfilgrastim biosimilar, Fulphila, in 

The first part of a 2-part story about the Indian biopharmaceutical industry and the regulatory limitations that affect its international marketing ambitions can be found 

Biocon said a subsidiary’s manufacturing centers in Bengaluru, India, were cleared by European Union authorities for biosimilar production.
 

Biocon Gains EU Manufacturing Certification for India Plants

International reference pricing (IRP), by which drug prices would be pegged to international standards, is under consideration in the United States, although it could lead to adverse long-term consequences, according to a panel of health care and economic experts who discussed the prospect at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) annual meeting, Virtual ISPOR 2020, held this week.

IRP may bring down the high cost of medicine for US consumers, but it could also stifle investment in new drug products because pharmaceutical companies would earn lower returns and have less money to invest in new medicines, said Lou Garrison, PhD, of the Comparative Health Outcomes, Policy, and Economics Institute Department of Pharmacy at the University of Washington in Seattle.

The intense clinical investigation to find a vaccine spurred by the coronavirus disease 2019 (COVID-19) pandemic illustrates how the US pharmaceutical industry is motivated to explore new therapies, he said. “Reference pricing is a poor and risky approach” to saving money for health care consumers, he noted.

IRP legislation has been introduced and passed in the House, Garrison noted. The Elijah E. Cummings Lower Drug Costs Now Act would allow HHS to 

 drug prices and establish an international drug index that would cap drug prices at 120% of prices in 6 selected countries. The Congressional Budget Office has forecast that this could save $456 billion over 10 years, although it would lead to 8 fewer drugs coming to market from 2020 to 2029.

United States residents pay, on average, 3 times more than Canadian citizens do, in terms of drug costs, and many European countries pay less than Canadian citizens, even though the national gross domestic product (GDP) per capita may be higher in those countries than in Canada, according to data presented during the discussion. For example, in Norway, the GDP per capita is more than twice that of Canada but the average drug price is roughly 75% that of Canada’s. Meanwhile, drug prices in the United States are soaring.

These issues notwithstanding, Garrison maintained that higher prices in the United States support innovation that would not occur otherwise. He cited one estimate that, on average, “$2.5 billion is required in additional revenue to support the invention of 1 new chemical entity.”

Pricing power granted to companies through product exclusivities in the United States “elicits a greater supply of new drugs in the long term, but…results in higher prices and, thus, worse access in the short term,” he said. “But if new medicines aren’t invented, no one can access them in the long term.”

In fact, panelists said, outside of the United States, in Europe, for example, IRP is seldom used alone. It may be used on a limited basis, and other pricing systems may be combined to make it workable, said Jaime Espin, PhD, BLaw, MScHE, a professor at the Andalusian School of Public Health in Granada, Spain.

One of the downsides of IRP in the countries that use it is that it creates a disincentive for pharmaceutical companies to launch their products in lower-drug-price countries, he said. These countries may be the last to see new products launched, the panelists noted. Further, there is a tendency for countries to peg their prices to the lowest prices elsewhere, which compounds issues of poor access and lack of innovation.  

A European Commission report cited by Espin indicated that the United Kingdom, Germany, and Sweden have freer pricing systems and are generally preferred by companies as product launch locations.

A lack of pricing transparency makes it difficult to understand IRP dynamics, and there is not enough “conclusive evidence” about IRP and its value, owing to a scarcity of investigation, the panelists noted.

Espin suggested that countries use IRP to negotiate or benchmark the prices of medicines and improve transparency. He also suggested that countries and payers choose comparator countries for IRP based on economic status, pharmaceutical pricing systems, actual versus negotiated prices, and other factors.

Panelist Zoltan Kalo, PhD, a health economist with the Center for Health Technology Assessment at Semmelweis University/Syreon Research Institute in Budapest, Hungary, said “inferior health outcomes” are one consequence of IRP, owing to access issues that arise. “Drugs might be available only for VIP patients,” he said. For this reason, he suggested avoiding IRP in lower-income countries, instead recommending that the salaries of nurses and physicians in lower-income countries be indexed according to international standards. This, he said, would prevent physicians and nurses from migrating across borders in search of higher pay. COVID-19, he said, has put a spotlight on how this dynamic has created a shortage of clinicians in Hungary.

Garrison L, Espin J, Kalo Z, Incze A. International reference pricing: US vs. rest of world—who is shooting whose foot? In: Proceedings from Virtual International Society for Pharmacoeconomics and Outcomes Research 2020; May 18-20, 2020; Orlando, FL. https://www.ispor.org/heor-resources/presentations-database/presentation/intl2020-3195/11541

There’s not enough study of the effects of international reference pricing, but it is likely to stifle innovation and create access problems, according to an expert panel at Virtual ISPOR 2020, the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research.
 