Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Health care consumers are routinely blitzed with advertisements by drug companies, so how are they to find out about biosimilars? And further, providers and payers aren’t necessarily going to agree on what drugs should be prescribed to patients. Should they be lowest-cost or should the manufacturer with the most reliable supply chain be granted preference on formulary?

A panel of industry experts moderated by an economist addressed these issues in a recent talk at the American Conference Institute’s 2021 Summit on Biosimilars and Innovator Biologics.

Interchangeability almost has become an unnecessary stumbling block to implementation of biologics and biosimilars

“The thing that sometimes is indicative of our market is that with so many different stakeholders, incentives are not always aligned,” said Ali Ahmed, senior vice president of biosimilars at Fresenius Kabi.

He joined panelists Terry Rea, vice chair of the Intellectual Property Group at Crowell & Moring in Washington, DC, and Sonia T. Oskouei, vice president of biosimilars at Cardinal Health, in the discussion conducted by Joseph P. Fuhr, professor emeritus of economics at Widener University.

“I’m afraid that consumers are overwhelmed with anecdotes on biosimilars. I mean, we advertise to them directly. We have insurance companies that advertise constantly on TV,” Rea said. The world was a lot simpler years ago, but things have gotten more specialized, and with that, complexity has crept in. “Our complex system is delaying getting good medications to patients.”

Kaiser Permanente is a managed care consortium that has had tremendous success in getting biosimilars into use by patients, but it’s the integrated nature of that network that has been key to this accomplishment, Ahmed said. “It’s not that I’m advocating for full integration of every health plan with a network, but it does show the power of aligning incentives.”

Six years after biosimilars first appeared in the United States, a new level of complexity is about to surface with the pending arrival of biosimilars designated as “interchangeable,” which would enable pharmacists to dispense them in place of originator biologics without a prescriber’s express authorization.

Panelists said the interchangeable designation has already added new wrinkles to biosimilar adoption. Manufacturers may not see any value in seeking interchangeable designations for their biosimilars, and they may not even qualify. The FDA requires studies to demonstrate no changes in outcomes for patients who switch multiple times between originator and biosimilar agents.

“Some of these products could be waiting a lifetime and not have that designation, and there continues to be a knowledge gap around what the designation means and the implications of it,” Oskouei said.

The first interchangeable insulin biosimilars are expected to be approved soon, and this will be an opportunity to observe how the interchangeable designation functions, particularly in the managed care setting, Oskouei said.

“If there’s ever an opportunity to bring more affordable medicine to diabetes care in the United States, this is a great, great event,” she said.

You can see good uptake of biosimilars in oncology, but the same is not true across the board, Ahmed said. “I’m not sure whether spending all that extra time doing the clinical trials to get that interchangeable designation is really worth the squeeze. It will really depend on product.

“Maybe in the autoimmune space there could be more value to it, although you could still argue that working closely with a pharmacy benefit manager and a payer to get a preferred formulary position would be actually more valuable than having an interchangeable designation,” he said.

I do think that the number of patents that protect some of these molecules extends the patent term, or the time of a period of exclusivity, far beyond anything that was expected in the beginning

Still, an interchangeable designation may mean less to a provider who is trained to consider the clinical evidence supporting a treatment and base medical decisions on that. As a manufacturer, “You might be better off investing in health economic data. You know, how many times does a patient have to return to the hospital or the clinic?” Ahmed said.

“Interchangeability almost has become an unnecessary stumbling block to implementation of biologics and biosimilars,” Rea said. “It’s actually misleading and frustrating.”

Interchangeability is not likely to cause payers to put more emphasis on use of biosimilars, Ahmed said, speaking from the manufacturer’s point of view. “I think adoption and pricing and manufacturing capabilities and who you are in the market in terms of having a sales force that can pull that drug through the channel” will be more important to whether a payer grants preferred access or, simply, formulary access, he said.

A real barrier to biosimilar use is the patent portfolios that originator companies acquire to protect their product exclusivity, Rea said.

“I’m primarily a patent attorney, and I’d like to see manufacturers or the innovators be limited with the number of patents or the patents they’d like to assert [in litigation], because right now I do think we are delaying the number of biosimilars that are on the market, or preventing companies from even getting into that space, because of the huge number of patents,” she said.

“I do think that the number of patents that protect some of these molecules extends the patent term or the time of a period of exclusivity, far beyond anything that was expected in the beginning,” she said.

Articles

Panelists at the American Conference Institute's 2021 meeting took on the complexities of biosimilar adoption in a wide-ranging discussion.  

ACI Panelists Discuss Misaligned Incentives in the Biosimilars Market

Studies of adalimumab biosimilars in the European Union and the United Kingdom evaluated comparability and patient acceptance following a switch from the originator product (Humira).

In a study of patients with inflammatory bowel disease who switched to an adalimumab biosimilar (SB5, Hadlima) after achieving stability on Humira, investigators concluded adalimumab trough levels were comparable at up to 1-year post-switch.

Trough levels describe the lowest concentration of drug prior to repeat dosing. “Adalimumab trough levels remain within the therapeutic range after switch from originator to [Hadlima],” authors of the study wrote.

Also, the proportion of patients with secondary loss of response (SLOR), or who lost response to the drug during maintenance treatment, was comparable to reported data for the originator drug. No changes in disease activity were observed for patients on Hadlima, based on disease activity scores and biochemical parameters.

The study, conducted in Belgium, enrolled 110 patients with Crohn disease (n = 84) and ulcerative colitis (n = 26). At 12 months from baseline, Hadlima treatment was discontinued in 5 patients because of high adalimumab antidrug antibodies. Investigators said 9 patients presented with SLOR, 3 of whom discontinued treatment.

Mean trough levels for Hadlima were 9.21 μg/mL at baseline, 9.16 μg/mL at week 8 (

Deprez N, De Somer T, Baert d, et al. Evaluation of trough level and disease activity after switch from adalimumab originator to biosimilar in patients with inflammatory bowel disease. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster 281.

Patients with inflammatory bowel disease (N = 110) were gauged according to their acceptance of a switch to an adalimumab biosimilar (SB5, Hadlima) after achieving disease stability on the originator product (Humira). Investigators reported an acceptance-of-switch rate of 79.3%.

The switch was optional and patient satisfaction was assessed at baseline and at 8 weeks, 6 months, and 1-year post-switch.

The most common reasons given for refusal to switch were fear of a disease flare (n = 8), ease for staying on the originator drug (n = 4), and lack of trust in biosimilars (n = 3). Patients who declined to switch numbered 15.

Investigators said no demographic factors were associated with a refusal to switch. At the end of the 1-year term, 28 patients had discontinued the biosimilar and the most common reasons given were high antidrug antibodies at baseline (n = 5), SLOR (n = 3), injection site pain (n = 8), and other adverse events not causally related to the biosimilar (n = 10).

Authors of the study reported that at the 1-year point, 74.5% of patients were still receiving treatment with the biosimilar.

Visual analogue scales (VAS), which are used to measure patient sentiment in cases where more reliable quantitative findings cannot be obtained, were used to measure local discomfort up to 30 minutes after injection. “The median VAS for local discomfort after 30 minutes was between 0 and 1/10 at all time points, which was not significantly different compared to the originator,” investigators wrote.

“Satisfaction with the decision to switch was high and remained stable over the different time points,” they wrote.

De Somer T, Deprez N, Deceuninck M, et al. Acceptance of switch, patient satisfaction and adverse events after switch from adalimumab originator to biosimilar SB5 in patients with inflammatory bowel disease in a real-life setting. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster 469.

An interim analysis of the PROPER study of patients with Crohn disease who transitioned to an adalimumab biosimilar (SB5, Hadlima) following treatment with the reference product (Humira) demonstrated that most patients had no meaningful difference in disease activity or Hadlima dosing regimen by week 48 following transition to the biosimilar.

Investigators also concluded that the COVID-19 pandemic had no apparent effect on Hadlima use in this cohort (n = 459) and no new safety concerns were detected.

Investigators said 45 patients discontinued Hadlima and 10 withdrew from the study by week 48. Disease flare was reported for 29 (6.3%) patients, 7 of whom changed biologic treatment and 22 did not; 2 had SLOR.

Investigators said 12 patients reported 13 serious adverse events, of which 4 were considered related to use of the biosimilar (anal fistula, 2 perianal abscesses, and subileus).

Dignass A, Gisbert J, Freudensprung U, Addison J. The PROPER study: interim analysis of a pan-European real-world study of SB5 adalimumab biosimilar after transition from reference adalimumab in patients with Crohn’s disease. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster 469.

Based on an ongoing crossover study enrolling patients with Crohn disease (N = 112) transitioning between Humira and the adalimumab biosimilar Imraldi, investigators concluded that despite limited knowledge and concerns about transitioning, patients generally accept the principals of biosimilars and can be reassured about receiving them.

The study is being conducted at University Hospital Southampton in the United Kingdom.

Among patients enrolled in the trial, investigators interviewed 35 on such topics as motivation to switch to a biosimilar, initial concerns, “reassuring factors,” and patient reflections on the experience.

Investigators noted that patients generally had little prior awareness of biosimilars but generally would accept a switch to biosimilar to minimize drug expense. “Prior to undertaking biosimilar transition away from the [originator brand], efficacy and adverse effects were common concerns for patients.”

Investigators reported that for patients to have confidence in biosimilars, they need to trust in their health care providers. They also stated that having a contact person on the health care team, education about biosimilars, and specific monitoring also provide reassurance.

“When reflecting on the experience, participants noted little subjective difference in efficacy or tolerability (although 22 participants specifically mentioned injection pain) following brand transition,” authors of the study wrote. “The majority feel comfortable with future transition to another adalimumab biosimilar.”

The investigators concluded that a tailored, patient-centered approach to using biosimilars is key to a successful switch.

Young D, Latter S, Harvey J, et al. IBD Reference and Biosimilar adalimumab CroSS over Study (iBaSS): a mixed methods clinical trial of patients transitioning between originator and biosimilar adalimumab. Qualitative findings from an interim analysis presenting the patient perspective. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster 585.

Presentations at the European Crohn's and Colitis Organization annual meeting supported the transition to adalimumab biosimilars and provided patient acceptance data. 

Adalimumab Biosimilar Transition Studies Reported at ECCO'21 Congress

Medicare would have saved $2.19 billion on adalimumab spending between 2016 and 2019 had biosimilars become available in the years they were approved, 

 who identified patent obstacles as the cause.

They made comparisons with the European Union system for biosimilar introduction and suggested various legislative reforms that would improve access to biosimilars in the United States.

“Delayed adalimumab biosimilar availability resulted in important forgone savings to Medicare that could have been allocated to other health services, highlighting the need for patent reform and legal changes to facilitate biosimilar availability in the United States,” authors of the study wrote.

During the study period, 5 adalimumab biosimilars were approved by the FDA. None will be marketed before 2023 owing to patent settlements with AbbVie, the adalimumab (Humira) originator company. “Although the main active ingredient patent in the United States expired in December 2016, AbbVie obtained over 100 additional US patents on the drug, ranging from manufacturing processes to new formulations,” the authors wrote.

In calculating the savings to Medicare, the authors assumed that the first biosimilar (Amjevita) would launch with a 25% price discount relative to Humira, with an additional 3.4% price discount per year. They assumed that each successive adalimumab biosimilar would result in a further 1.7% price discount upon market entry. They based those assumptions on a study of biosimilar launch prices in the European Union.

Delayed adalimumab biosimilar availability resulted in important forgone savings to Medicare that could have been allocated to other health services, highlighting the need for patent reform and legal changes to facilitate biosimilar availability in the United States

They assumed that by 2019 the 5 approved adalimumab biosimilars (through 2019) would have achieved a 42.9% price discount relative to Humira. They also assumed that the presence of the biosimilars in the marketplace would cause the Humira price to drop 3.5% each year, resulting in a 21.3% lower Humira price by December 2019.

Actual Medicare payments for Humira products from 2016 to 2019 increased from $1.75 billion in 2016 to $2.47 billion in 2019. This was owing to price increases by AbbVie as well as an increase in the units of product sold, according to the authors. During the 4-year period, net prices per unit, which included syringe and pen formulations of adalimumab, increased from $1571 to $1752.

“Had adalimumab biosimilar products launched immediately upon approval, estimated Medicare nonrebate spending on them would have been $18.3 million in 2016, $225.7 million in 2017, $436.2 million in 2018, and $727.7 million in 2019,” they wrote.

During that same time, Medicare nonrebate Humira spending would have declined from $2.33 billion to $1.42 billion annually, they said.

Under their scenario of earlier biosimilar introduction, cumulative Medicare spending on adalimumab from 2016 to 2019 would have been $8.98 billion instead of $12.11 billion.

“Our estimates were likely conservative,” the authors wrote. They expected US adalimumab biosimilars to capture 46% of the US market by 3 years after first launch. But in the United Kingdom, adalimumab biosimilars captured over 63% of the market within 6 months after first launch and over 50% of the German market 1 year after first launch.

They also estimated that US biosimilar competition would drive down Humira prices 21.3% by December 2019, but in some EU countries, adalimumab biosimilars have driven down Humira costs by 80% of prebiosimilar pricing. “These observations suggest that even greater savings than calculated in our study may have been possible from timely adalimumab biosimilar entry in the United States.”

The authors offered support for various reforms that would remove patent obstacles, such as a proposal for allowing originator products exclusivity protection for just 1 key patent filed before FDA approval 

. “Alternatively, manufacturers could be free to secure any number of patents on their product but to claim infringement on only a few,” they wrote.

They also recommended strengthening of antitrust laws, noting that California has tightened up allowances for settlements between originator companies and biosimilar developers. This law has a stronger presumption of anticompetitiveness where transfers of value between originator companies and generic or biosimilar companies are involved.

The authors concluded that the loss of the potential $2.19 billion in savings from 2016 to 2019 from adalimumab biosimilars was costly in that those savings might have expanded access to “commonly underfunded services, such as preventive, behavioral, and hospice care.”

Medicare lost out on over $2 billion in savings as adalimumab biosimilars were sidelined by patent restrictions, said investigators who recommended patent reforms.  

Study: Medicare's Lost Savings Due to Delayed Adalimumab Biosimilar Entry

Two companies have entered a commercialization deal for what they said would be the first darbepoetin alfa biosimilar distributed in the Persian Gulf. Darbepoetin alfa is intended for the treatment of anemia associated with chronic renal failure. In the United States, darbepoetin alfa is distributed as Aranesp, an originator product.

The biosimilar (Nesbell) is currently approved in the Republic of Korea and would be marketed by Menagen Pharmaceutical Industries in the 7-member Arab states of the Persian Gulf: Bahrain, Kuwait, Iraq, Oman, Qatar, Saudi Arabia, and the United Arab Emirates.

The other partner to the deal is Chong Kun Dang Pharmaceutical (CKD), of Republic of Korea. “Through this collaboration with CKD we are establishing our biosimilar footprint in Middle East and Africa markets and reaching more people living with severe chronic diseases. We aim to provide broad accesses to patients with unmet medical needs by leveraging Menagen’s local expertise and capabilities,” CKD said in a 

Menagen was described as a biomanufacturing facility based in Muscat, Oman, with plans to expand operations into agents for oncology, hematology, nephrology, and other various medicines. These would include biosimilars and orphan drugs.

Chong Kun Dang of the Republic of Korea has entered a licensing deal for the distribution of a darbepoetin alfa biosimilar in the Gulf region. 

Darbepoetin Alfa Biosimilar Is on Tap for Persian Gulf

No new biosimilars have been approved so far in 2021, and the number of approvals in 2020 (3) was low compared with previous years; but 6 years after its first biosimilar launch, the United States is ahead of where the European Union was, according to a 

of Amgen’s 2021 Biosimilar Trends Report.

Further, biosimilars are launching at deep discounts to reference products and capturing increasing market share, the preview states. 

The European Union approved its first biosimilar in 2006 (somatropin), and 6 years later, the European market had just 11 biosimilars approved vs 29 for the United States (

Although 8 of the 29 approved US biosimilars won’t be launched before 2023, that still leaves 21 biosimilars in the marketplace so far. The only biosimilar launched in 2021 has been Riabni, Amgen’s rituximab agent. The FDA approved Riabni for marketing in December 2020.

“Data show that the US biosimilar landscape is advancing faster than the European Union biosimilar landscape [did]", according to the Amgen preview. There are currently 65 biosimilars approved in the European Union.

The full 2021 Biosimilar Trends Report is expected to be published in the autumn of 2021.

The preview measures the difference in wholesale acquisition costs (WACs) for biosimilars vs originator drugs. WACs are the list prices that manufacturers charge wholesalers, although these do not include rebates and discounts provided by the manufacturer, which are important for a precise understanding of what wholesalers are paying.

WACs for biosimilars are sometimes well below WACs for reference products, according to Amgen. For example, the WAC for Avsola (infliximab; Amgen) was 57% below the reference product (Remicade) price WAC when the biosimilar was launched in July 2020.

Four pegfilgrastim biosimilars were launched from July 2018 to June 2020, and these were issued at WAC discounts of 33% to 37%, according to the preview. During that time, the average selling price (ASP) for the originator product, Neulasta, dropped by 35%. The ASP is the manufacturer average price minus rebates and discounts.

“The rate of biosimilar uptake is generally increasing over time....Additionally, first-to-launch biosimilars tend to capture a greater portion of [market share] compared with later entrants.

In the case of infliximab biosimilars, the discounts have been significantly deeper with each successive biosimilar introduced to market; however, the time period involved (late 2016 to mid-2020) was longer and ASP prices for the reference product, Remicade, have dropped roughly 45% since the first infliximab biosimilar launch.

The introduction of trastuzumab biosimilars, from July 2019 to April 2020, was marked by significantly more modest WAC discounts of 10% to 22%, according to the report. Meanwhile, the reference product (Herceptin) ASP dropped 5% or less, Amgen said.

Amgen also compared biosimilar WACs with reference product ASPs, demonstrating that, at the wholesale level, biosimilars were introduced for less than reference product prices net of discounts or rebates.

The most dramatic example was for the filgrastim biosimilar Nivestym, which was introduced at a WAC 24% below the reference product (Neupogen) ASP.

The preview notes that biosimilar prices are decreasing at an annual rate of 10% to 15%.

The report also states that biosimilars launched in the past 2 years have achieved a significantly larger average market share (61%) vs biosimilars launched prior to 2019 (13%). “The rate of biosimilar uptake is generally increasing over time.... Additionally, first-to-launch biosimilars tend to capture a greater portion of [market share] compared with later entrants,” Amgen said.

Filgrastim biosimilars have captured the largest share of their respective market (73%) and infliximab biosimilars, the lowest (23%).

For an interview with Christophe Bourdon, senior vice president and general manager of US Oncology for Amgen, about the rollout of Riabni, click 

Biosimilars are launching at significant discounts to reference products and capturing increasing market share, according to an Amgen report. 

Amgen US Biosimilar Trends Report Highlights Price Discounts

Two former officials of JHL Biotech, formerly of Zhubei, Taiwan, are 

 to have stolen trade secrets relating to biosimilar manufacture from Genentech, and a former Genentech principal scientist and her husband have 

 to conspiring to assist them, according to an unsealed indictment and statement from the US Attorney’s Office for the Northern District of California.

Raco Ivanov Jordanov, 73, of Rancho Santa Fe, California, co-founder and former CEO of JHL and Rose Lin, 72, of South San Francisco, California, another company co-founder and former company chief operating officer, are alleged to have also committed wire fraud exceeding $101 million.

The unsealed indictment alleges that the two worked with insiders at Genentech in San Francisco, California, to steal thousands of confidential and proprietary documents from Genentech that enabled JHL to accelerate its development and production of biosimilars of Genentech agents. JHL is alleged to have used the advantage it gained to obtain a lucrative biosimilar development deal with Sanofi.

At the time, JHL was working on biosimilars for rituximab (Rituxan), trastuzumab (Herceptin), and bevacizumab (Avastin).

The indictment states that the scheme began in 2009 when Lin recruited a scientist at Genentech and her husband to steal confidential information. Those secrets helped JHL to “cut corners, reduce costs, solve problems, save time, and otherwise accelerate product development timelines,” the indictment states.

The alleged perpetrators were said to have taken documents covering Genentech’s standard operating procedures and pasted JHL logos over them and passed them off as JHL standard procedures. The partnership with Sanofi, a Paris, France-based company, was for the manufacture and distribution of biosimilars in China. That deal was signed in 2016.

“Sanofi allegedly paid $101 million to JHL Biotech, using foreign and interstate wires to carry out the corporate transaction. This cash payment allegedly was part of a strategic relationship worth potentially $337 million to JHL Biotech,” the indictment states.

Upon disclosure of some of the aspects for the above-described allegations, in 2019, JHL’s stock valuation, once as high as $916 million, crashed. The company later renamed itself and divided into 2 companies: Eden Biologics and Chime Biologics, both of Wuhan, China.

In tandem with the indictment, the US Attorney’s Office also 

 that Xanthe Lam and her husband Allen Lam, who worked in the Quality Control Department at Genentech, have pleaded guilty to conspiracy and other charges related to the theft of trade secrets from Genentech.

Top executives of JHL Biotech are alleged to have conspired to steal secrets for development of rituximab, bevacizumab, and trastuzumab biosimilars. Two co-conspirators have pleaded guilty in the case. 

Former JHL Biotech Officials Indicted in Theft of Trade Secrets From Genentech

In the European Union, public panic over drug shortages caused by the COVID-19 pandemic drove demand for some drugs to 900% above normal, according to Adrian van den Hoven, director general of Medicines for Europe. “That’s not something that you have lying around in stockpiles.”

He spoke in a recent International Generic and Biosimilar Medicines Association (IGBA) panel discussion about trends affecting the generics and biosimilars industry. The occasion was IGBA’s launch of a whitepaper on industry sustainability.

Governments responded to drug shortages with calls for the pharmaceutical industry to shore up supply chains and geographically diversify manufacturing operations, although IGBA contends this may be expecting too much of the private sector.

“A lot of governments think that by snapping their fingers, this is going to happen, when in reality this will require investment by the private sector, even when there is some support for technology from government programs,” van den Hoven said.

The US government has urged that domestic drug manufacturing be expanded, although there’s a growing recognition among US officials “that we operate in a globalized world,” and part of that is an appreciation for ensuring that the United States and its allies abroad have resilient supply chains, said Jonathan Kimball, vice president, Trade and International Affairs, Association for Accessible Medicines.

Concurrent with this push to expand production capacity is a downward pressure on prices by payers that erodes the margin of return, IGBA contends.

“The real challenge is that the markets are currently designed to drive prices as low as they possibly can go, and of course, that’s not compatible with the diversity [local production] model, so I think we have to have sustainable market models that encourage those investments,” van den Hoven said.

The market drives prices down, but at the same time, there is increased market demand for what is viewed as a diversified, secure supply chain.

Kimball responded that the pharmaceutical industry can defend against pricing pressure by improving the reliability of its drug supply chains and commoditizing that. “The market drives prices down, but at the same time, there is increased market demand for what is viewed as a diversified, secure supply chain.”

Meanwhile, there are innovations that were implemented during the pandemic to resolve supply problems, and these could be employed on an ongoing basis to streamline the flow of drugs across borders, panelists said.

Temporary imports and the reimportation of drugs previously exported were some of the resupply measures tried with success during the pandemic, van den Hoven said.

Also, digital systems for expediting international shipments helped improve the allocation of drugs to where they were most needed, and this innovation could be extrapolated for future needs, he said. “The movement of product across countries will benefit the industry significantly, but more importantly, it will reduce the risks of localized knockout in certain countries. You’re able to move products much, much faster.

“Inside the European Union, we still don’t have it perfect, even within what is considered to be a single market,” van den Hoven said.

Over the long term, the generic and biosimilar drug marketplace is going to need support, the panelists said. In the European Union, government entities have slowly recognized the importance of a focus on patient acceptance of biosimilars and not just price, van den Hoven said.

In the United States, patient populations are relatively smaller for biologics than for generics, so the challenge is assembling sufficiently large populations for clinical trials, and after that, there may be only a small market of consumers for an approved biologics, Kimball said.

Patents on originator drugs add to the uncertainty surrounding making reliable projections about how successful a drug development program is going to be, he said.

But patents are a problem “the [US] government’s going to have to address, because they’re spending more and more of their health care resources on these complex products,” Kimball said. He cited a recent report that showed Merck has filed 129 patent applications on pembrolizumab (Keytruda) and the FDA has granted 86 of them, which is a formidable barrier to bringing a biosimilar to market.

Keytruda was originally approved in the United States for advanced melanoma in 2014. Its list of 

 now stretches to more than 30 settings and combinations. Keytruda’s worldwide sales in 2020 were $14.4 billion, according to Merck.

“If you’re a biosimilar producer, you have to feel confident that if you litigate those patents you’re going to be 100% successful, and the originator company just has to be successful in defending one of those patents to forestall biosimilar entry,” Kimball said.

When you look at the list of essential medicines, those that are most critical for health emergencies and for the US health care system, those are the products that tend to be high volume, low value, low-priced products. Those are the same products where prices have eroded to such a degree that you’re seeing shortages in the marketplace.

Too much payer emphasis on price reduction may drive producers out of the marketplace, Adrian said.

“I think the challenge we face is that a lot of payers and health ministries are obsessed with the lowest unit price of any molecule. You see it even in the private markets, for example in the United States. This is simply incompatible with the sustainability of the industry. We cannot invest in this kind of framework,” Adrian said.

In the United States, the unsustainability of an emphasis on prices is evident in medicines that are difficult to procure, Kimball said.

“When you look at the list of essential medicines, those that are most critical for health emergencies and for the US health care system, those are the products that tend to be high-volume, low value, low-priced products. Those are the same products where prices have eroded to such a degree that you’re seeing shortages in the marketplace.

“It’s not an issue of does the company want to produce these products. The question is, is it actually feasible for companies to manufacture certain products in certain markets?” Kimball said.

For a summary story on the contents of the IGBA whitepaper, click 

Following the release of a whitepaper on sustainable generics and biosimilars markets, members of a trade association discussed concerning trends for the industry. 

Panel Discusses Generic, Biosimilar Marketplace Sustainability

When COVID-19 first hit, individuals responded by hoarding drugs and countries began to talk of protectionist measures. Some, including the United States, responded with calls to strengthen domestic pharmaceutical manufacturing to protect against sudden disruptions in drug supply.

However, local drug manufacturing may be impractical and could lead to higher costs and further shortages, the International Generic and Biosimilar Medicines Association (IGBA), a trade association of generics and biosimilars producers, contends in 

A radical and uncoordinated shift to fully localized manufacturing would have detrimental effects on the Generics and Biosimilars industry by driving cost increases and ultimately endangering global access to medicines. No region is currently self-sustaining, and the industry will perform at its best if it can leverage the specific cost, capacity and capability advantages offered by players across various regions.

“While the pandemic has revealed the vulnerability of global supply chains, a radical and uncoordinated shift to fully localized manufacturing would have detrimental effects on the generics and biosimilars industry by driving cost increases and ultimately endangering global access to medicines,” the group states.

The group argues that manufacturers may not be able to scale up pharmaceutical plants in individual markets and that governmental pressure to foster local pharmaceutical manufacturing and supply chain reinforcement puts most of the expense and burden on companies that, at the same time, are contending with downward pricing pressures that limit their resources for infrastructure development.

Their paper looks at trends affecting the production and competitiveness of generic and biosimilar medications and recommends policy solutions to help with the sustainability and success of these lower-cost products.

The group calls for alignment of regulatory guidelines across global markets to make it easier for manufacturers to participate in diverse regional economies. “Convergence of approval pathways across markets will enable more cost-effective development by removing the need for market-specific development.”

They also argue for greater reliance on advanced analytical techniques (as opposed to clinical trials involving patients) for qualifying biosimilars for marketing approval. “Increasingly advanced analytical technology will be applicable to demonstrate robust evidence of biosimilarity,” they state.

“Consistent recognition of this fact across markets would significantly simplify development processes for biosimilar companies and free up substantial resources for new product development. Similarly, requirements for large-scale, patient end point studies for complex generics such as inhalers and long-acting injectables need to be revisited.”

Generics and Biosimilars companies can only live up to their vision of expanding patient access to high-quality and affordable medicines if they are granted the chance to market their products as soon as appropriate protection periods for originator products have expired.

The IGBA paper addresses heavy patenting of drugs by originator companies, a process they say regulators and legislators ought to counter by placing limits on product exclusivity. “Generic and biosimilar companies can only live up to their vision of expanding patient access to high-quality and affordable medicines if they are granted the chance to market their products as soon as appropriate protection periods for originator products have expired,” they wrote.

Capping exclusivity periods in a “timely” way would accomplish 2 objectives, they said. First, it would induce generics and biosimilars producers to bring competing, lower-cost products to market; and second, it would spur originator companies to devote their resources to pursuing “the next level of development innovation,” or better drugs.

In accord with such an objective would be the establishment of “internationally consistent” approaches to granting patent protections to originator products and well-aligned litigation systems across national borders so that patent protections can be challenged, IGBA says in the paper.

The group estimates that the US health care system saved $313 billion in 2019 by using generics and another $2.2 billion from biosimilars. In the European Union, where biosimilars are more widely used, the market for biosimilars measures $9.9 billion and amounts to 8% of the total biologics market.

EU biosimilar list price reductions appear to have cut medical spending by 5% since 2014 and “up to 67% for established classes such as erythropoetin,” the group states, although it says the actual reductions might be greater if privately negotiated drug price reductions are included.

The group states that biosimilar adoption has accelerated and in some markets “has reached high levels.” In Germany, for instance, biosimilar versions of adalimumab, bevacizumab, and rituximab account for 72%, 80%, and 85% of market share, respectively.

Despite negative factors cited above, the group says that double digit growth in the global biosimilars market is likely.

Companies will also need to leverage the full potential of data and analytics in the manufacturing and supply operations. Advanced analytics and artificial intelligence can come together to improve demand and supply planning, resulting in improved forecast accuracy, lesser inventory, and more capacity.

Much of the drive for this expansion will come from favorable regulatory policies and increasing stakeholder acceptance in the United States, the group says. “As a result, cumulative savings from biosimilars are expected to reach $285 billion globally over the next 5 years, with annual savings exceeding $100 billion in 2025 alone.”

But competition and downward pricing pressure, such as the European tender system of awarding supply contracts only to limited numbers of manufacturers, increases the risks and potential loss, such that only the first biosimilar entrants in a market may actually recoup their costs of development, IGBA states.

“Biosimilar launches have witnessed accelerated price erosion curves across markets. In recent [anti-tumor necrosis factor] product launches, erosion of prices reaches 25% on average at the time of entry of the first biosimilar. In products with a significant number of competitors (5 or more) and market modalities making strong use of tenders, erosion can reach up to 70% relatively quickly,” IGBA says.

If the pricing pressure is not managed well, “this could create unfavorable economics and lead to significant negative impact on availability and access of critical products,” the group says.

In a white paper, the International Generic and Biosimilar Medicines Association (IGBA) describes industry dynamics that it says affect market sustainability and patient access. 

IGBA Takes Aim at Pricing Pressure and Post–COVID-19 Protectionism 

with Teva Pharmaceutical Industries to commercialize a ranibizumab biosimilar candidate (FYB201) in the European Union, Canada, Israel, and New Zealand. Bioeq is a joint venture between Polpharma Biologics Group and Santo Holding.

The biosimilar candidate references the ophthalmologic agent Lucentis and is intended for the treatment of neovascular (“wet”) age-related macular degeneration (nAMD). In nAMD, abnormal growth of blood vessels under the macula and retina lead to swelling and bleeding that changes the position of the macula and distorts or clouds central vision.

“Worldwide, at least 25 to 30 million people are affected by age-related macular degeneration. The launch of a biosimilar ranibizumab can increase market competition, reduce cost, and expand patient access with proven analytical and clinical similarity to the original product,” Polpharma, a Warsaw, Poland-based company, said in a statement.

Bioeq has previously contracted with Coherus BioSciences, of Redwood City, California, for the distribution of FYB201 in the United States.

Bioeq does not yet have regulatory approvals for the marketing of FYB201, although it has reached the biologics license application submission stage, according to Polpharma.

Bioeq has previously received development guidance from the FDA and the European Medicines Agency regarding preclinical and clinical development of this potential biosimilar.

A multi-country phase 3 trial was begun in 2015 and Bioeq was hopeful that this would demonstrate equivalency of FY201 to Lucentis and lead to regulatory approvals. Polpharma said the phase 3 clinical assessments for FYB201 have demonstrated comparable efficacy in patients with nAMD.

FYB201 was originally licensed from Formycon, a German company, and subsequently developed by Bioeq.

Bioeq has anticipated commercialization in the United States as early as 2020 and in the European Union in 2022; however, neither geographic area has yet approved a ranibizumab biosimilar.

The company has also been working to develop an aflibercept biosimilar, referencing Eylea. That developmental agent, FYB203, also was licensed from Formycon and is intended for the treatment of nAMD.

Also, Polpharma is developing biosimilar versions of natalizumab (Tysabri; multiple sclerosis), vedolizumab (Entyvio; immunology) and ipilimumab (Yervoy; oncology). Of these, the natalizumab candidate is furthest along in development, having reached the clinical development stage.

Ahead of receiving regulatory approval for a "wet" age-related macular degeneration biosimilar candidate, a broad-based commercialization deal is inked. 

Bioeq Signs Another Marketing Deal for Ranibizumab Candidate

Gan & Lee Pharmaceuticals said positive phase 1 clinical results were 

for 3 insulin analog biosimilar candidates: insulin aspart (GL-ASP), insulin lispro (GL-LIS), and insulin glargine (GL-GLA), referencing NovoRapid, Humalog, and Lantus, respectively.

Although 2021 marks the centenary of insulin's discovery, insulin access remains a global health issue.

The results were presented at Scientific Sessions of the American Diabetes Association, held June 25-29, 2021. The company said all 3 studies met their primary pharmacokinetic (PK) and pharmacodynamic (PD) end points.

“These data demonstrate PK and PD bioequivalence between each of the proposed biosimilar Gan & Lee insulins and their respective reference compounds. In addition, the safety profiles were comparable,” according to a company statement.

Currently, there are no insulin biosimilars available in the United States, although the second half of 2021 is expected to produce at least 2 approvals.

 enrolled 36 health male volunteers who each received a single dose of either the biosimilar candidate or the US or EU versions of NovoRapid (rapid acting) in each of the 3 euglycemic glucose “clamp” periods. The clamp technique maintains blood glucose concentrations at predefined target levels to allow assessments of insulin action.

Investigators said the aspart concentration and glucose infusion rate profiles between products were “superimposable” in terms of comparability. PK biosimilarity was demonstrated in terms of serum aspart concentration, and primary PD end points and sensitivity analyses also demonstrated equivalence.

They said adverse events (AEs) were rare with just 7 to 14 AEs per insulin and just 1 injection site reaction with GL-ASP (mild erythema).

compared PK and PD properties of GL-LIS with the US and EU versions of Humalog, a fast-acting insulin, in 38 healthy male volunteers.

Investigators said each participant received a single 0.2 U/kg dose of 1 the 3 formulations in each of the 3 euglycemic glucose clamp periods. Serum lispro concentration and glucose infusion rate profiles were “superimposable, demonstrating biosimilarity, they said.

Serum lispro concentration point estimates were close to 100% between the biosimilar candidate and the reference versions, and the 90% CIs were within predefined similarity margins of 80% to 125%. Primary PD and secondary PK/PD end points met biosimilarity criteria, as did sensitivity analyses.

Investigators reported a low incidence of AEs (5-11 AEs per insulin). There were no injection site reactions.

 of GL-GLA vs the US and EU versions of Lantus (glargine, long acting) was conducted in 114 healthy male volunteers with type 1 diabetes. Participants received a single dose (0.5 U/kg) of GL-GLA or the US or EU versions of Lantus in each of the 3 euglycemic glucose clamp periods.

Investigators said the PK and glucose infusion rates were “superimposable,” point estimates for measured metabolite M1 were close to 100%, and the 90% CIs were well within the predefined similarity margins of 80% to 125%.

They said the primary and secondary PK/PD end points were met and all insulins were well tolerated with matching AE rates of 19%, 26% and 21% for GL-GLA, and the US and EU formulations of Lantus, respectively. There were few injection site reactions per insulin.

Insulin aspart, lispro, and glargine biosimilar candidates referencing NovoRapid, Humalog, and Lantus demonstrated bioequivalence in trial data presented at the Scientific Sessions of the American Diabetes Association. 