Articles

Opinions are diverse on how best to clear the obstructions to biosimilar market entry and patient access. 

Poll: What Is the Best Way to Improve Biosimilar Access?

Tony Hagen is senior managing editor for The Center for Biosimilars

This is the second of a 2-part series on a study from the independent research center NORC at University of Chicago concerning biosimilar acceptance and uptake.

NORC: Pricing Transparency Could Aid Biosimilar Uptake

This is the first of a 2-part series on a study from the independent research center NORC at University of Chicago concerning biosimilar acceptance and uptake.

NORC: Doctors Must Overcome Patient Hesitation on Biosimilars

Shanghai Henlius Biotech says the market for a checkpoint inhibitor in China is wide open, and Biogen and Bio-Thera stake out a global map for their tocilizumab biosimilar.

News Roundup: Bio-Thera, Henlius Advance Biologics Development 

To overcome provider and patient preferences for brand originators, there has to be more of an incentive to use biosimilars, explains Nedzad Pojskic, PhD, MSc, Green Shield Canada.

Green Shield Canada: Preferential Status Is Vital to Biosimilar Uptake

In March 2021, the National Comprehensive Cancer Network’s (NCCN) Oncology Research Program, in partnership with Pfizer, announced that 10 research projects have been chosen to receive funding to focus on innovative ways to improve biosimilar adoption in the oncology space.

For this 3-part series of Not So Different, The Center for Biosimilars® has chosen projects that relate to improving perception of biosimilars, choice of biosimilars, and payer preferences for biosimilars.

In this first part, we spoke with Claire Saxton, vice president of education at Cancer Support Community, a worldwide patient and family advocacy organization that provides financial support and navigation services. Saxton discussed how her project titled “Frankly Speaking About Cancer: Biosimilars—Researching Oncology Patient and Caregiver Perceptions”will help address the current perception issues surrounding biosimilars.

For more on biosimilar perception, click 

For more on NCCN’s biosimilar work, click 

Podcasts

This is part 1 of a series on National Comprehensive Cancer Network/Pfizer efforts to investigate issues of importance to biosimilar stakeholders. 

Not So Different: How to Improve Perception Hurdles to Biosimilar Adoption 

Paul Cornes, BM, BCH, MA, MRCP, FRCR, is a consultant oncologist and biosimilars expert who was part of the team that developed and presented evidence to the FDA for the first successfullly approved US biosimilar.

Editor's Note: This commentary by Paul Cornes, MD, BCH, MA, MRCP, FRCR, is in response to a 

 about copy biologics produced in India and efforts to bring them up to international standards of quality.

Reviewing papers on biosimilar medicines in India is always fraught with difficulties because there are 2 meanings of biosimilar. The first is a strict regulatory term meaning follow-on biologic approved by the multistep biosimilar regulatory pathway pioneered by the European Medicines Agency and now adopted as the World Health Organization (WHO) standard. Similarly, rigorous pathways have been applied in economically developed countries such as the United States, Canada, Japan, Australia, and New Zealand. The second use, or misuse, is a broad marketing term for any follow-on biologic brand made and approved to any standard.

Importantly, India itself has never approved a biosimilar. Instead, the Indian regulator, the Central Drugs Standard Control Organization (CDSCO), approves follow-on brands of biologics as Indian similar biologics, or ISBs. The distinction is important, because the regulatory standards in India still lie below the WHO benchmark. This situation led to criticism of ISB regulations by the Indian Parliamentary Standing Committee on Health and Family Welfare that oversees the CDSCO, as well as action in India’s High Court. One example might serve to illustrate the problem: the average clinical confirmatory trial for a trastuzumab biosimilar in Europe had more than 640 participants, whereas for ISBs, the numbers were often just above 100.

This doesn’t mean the resulting medicines from India are necessarily good or bad; they simply lack the assessment needed to deliver the predictability required of WHO standard biosimilars. The European regulator has called this approach scientifically unacceptable. The best term for this lesser class of follow-on biologics is more properly 

 the reference biologic but fell short of the biosimilar standard. Other terms that have been used are 

. We know little about these drugs in practice, and what little we do know is often of concern; for example, the Malaysian regulator reviewed multiple intended copy biologics from Asia and found significant issues for all the drugs assessed and listed these problems in a 

This is similar to the experience of our group. We have just completed the largest-ever survey of intended copy biologics, and the resulting series of papers is at the stage of internal peer review with colleagues before submission in 2021. Importantly, we find that this situation can be unfair on Indian manufacturers who have delivered follow-on biologics to the WHO standards we require. For example, a trastuzumab biosimilar from Mylan/Biocon and filgrastim and pegfilgrastim biosimilars from Intas/Accord were developed in India and are approved as biosimilars in Europe and beyond. However, in both those situations, the biosimilar standard approval was made by regulators in Europe and the United States, not India.

Biosimilars approved by the European regulatory pathway are proven to meet the standards we require in practice. Now, with more than 70 biosimilars approved, more than 2 billion documented patient days of exposure to European biosimilars, and more than 178 studies of brand switching to biosimilars, we can be confident that the quality, safety, and efficacy of European-approved biosimilars match the reference biologics’ with no clinically significant differences.

Intended copy biologics create a problem for pharmacists and physicians in less-regulated regions of the world because selecting follow-on biologics requires an ability to differentiate originator reference biologics, biosimilars, and intended copy biologics from one another. Then, because intended copy biologics represent such a heterogenous group of products, the decision to use them places significant pressure on the prescriber to understand the development and regulation of each product through a detailed study of the drug’s development and regulatory dossier. Unlike the public assessment reports of Europe’s regulator, or the FDA Advisory Committee briefing documents on biosimilars, our experience in finding such a document for an intended copy biologic is that almost none are accessible in the public domain. The lack of differentiation also creates a problem for pharmacovigilance. In a recent 

 from our group, we discovered that even the Indian Pharmacopoeia Commission was uncertain of the differences and linked unexpected adverse event reporting to the incorrect class of medicines.

It is therefore heartening to read a paper from India that begins to describe the issues involved in discriminating between these different classes of biologic medicines and why these matter. We should congratulate Ramesh Jois and colleagues for their 

. They explain the problem of differentiating between original reference biologics, biosimilars, and biomimics or 

when discussing biologic medicines in India.

Biosimilar regulators in Europe and the United States typically review between 60 and 100 tests of equivalence between a proposed biosimilar and its reference biologic. They also oversee the regulatory trials and inspect the production and distribution standards of the drug as well as monitor pharmacovigilance and product changes over the drug’s lifetime. This takes well-resourced regulators in Europe and the United States about 1 year for each biosimilar application, which is equivalent to the amount of time to that needed to assess a novel drug.

Those of us living and working in regions with well-equipped regulators and high standards should take a moment to appreciate our fortunate situation. Only a minority of the world’s nations are able to invest the considerable resources and educate the highly trained staff to deliver such regulatory standards. We should pay tribute to the WHO, which has been running regulatory workshops worldwide to raise attention to these problems.

The WHO has also proposed a solution, by offering to “prequalify” biosimilar versions of brands included in their list of essential medicines so that less-well-supported regulators have products with the necessary standards already listed for use. Many other nations have adopted a “trusted coregulator” approach and offer rapid assessment of follow-on biologic brands that have already gained biosimilar approval in Europe and the United States.

To their credit, the CDSCO has responded to criticism by raising its standards with guidance posted in 2012 and updated in 2016, a process that I am sure will continue until India, too, matches the WHO requirements. Until then, readers and prescribers need to be able to differentiate between biosimilars as a strict regulatory term and the marketing claims made on behalf of intended copy biologics.

An internationally recognized authority on biosimilar development discusses varieties of copy biologics in India and the need to distinguish these from true biosimilars.

Column: India Struggles to Meet International Biologics Standards

The Center for Biosimilars® has launched “Biosimilars 101: Practice Concerns, Market Acceptance, and the Biosimilars Pipeline,” an e-book resource for the health care community. This publication contains insightful analysis and guidance from key opinion leaders who are actively engaged in the day-to-day effort to understand biosimilar trends and bring these lower-cost agents to patients who need them.

“Biosimilars 101: Practice Concerns, Market Acceptance, and the Biosimilars Pipeline,” answers some of the most basic and common questions about these important agents: How should the patient-physician conversation about these agents be addressed? What biosimilars are available, and in what disease categories will they be available next? Have biosimilars been accepted, and what roadmap should a health care institution follow to achieve greater biosimilar savings and access for patients? And finally, where did biosimilars come from? What was the legislative intent and regulatory foundation that led to the development of an approval pathway for these copy biologics?

Biosimilars are approved by regulators as safe and efficacious versions of originator biologics with no clinically meaningful differences. Their acceptance and use in the United States and Europe has grown rapidly, and the number of companies worldwide that are joining the effort to produce these more-economical agents bodes well for efforts to bring down the soaring cost of biologics. Biosimilars accounted for $2.2 billion of savings on health care costs in the United States in 2019, according to the Association for Accessible Medicines. There is potential for even greater savings.

by Dan Kistner, group senior vice president for Pharmacy Solutions at Vizient, “One of the keys to managing costs for health systems is the adoption of biosimilars as they come on the market. There are now 12 biosimilars available and where there are 2 or more competitors, we have seen prices as much as 30% lower than the branded product. Providers and payers must now become better aligned to realize the full benefit that competition can offer in driving down the cost of care.”

“Biosimilars 101: Practice Concerns, Market Acceptance, and the Biosimilars Pipeline” is chock-full of helpful information for the health care provider, patient advocate, practice administrator, or industry professional who needs to keep up with developments in biosimilars or employ them for greater savings and access. Obtain your copy by clicking 

The latest e-book from The Center for Biosimilars® offers insightful content on patient education, biosimilar development, and regulatory issues. 

The Center for Biosimilars® Launches Education e-Book for Biosimilar Stakeholders

Providers and health care institutions are going to need a lot more real-world data on how patients respond to various biosimilars and switches between biosimilars and reference products, according to a varied panel of private practice, academic hospital, and group purchasing organization experts in a discussion at the Community Oncology Alliance virtual Community Oncology Conference 2021.

“If we can solve the issue of real-world evidence and data and supply that, I think that will support the use of biosimilars moving forward,” said Sandeep Parsad, PharmD, MBA, BCOP, assistant director of pharmacy at University of Chicago Medicine (UCM).

Providers are going to need convincing, particularly as the choices among biosimilars become more numerous, the panel said. In the oncology space, biosimilars as therapeutic drugs are fairly new, although in supportive care these have been used much longer. And it is often stated that oncologists, especially, become more circumspect in the disease setting about the choice of agents, preferring to go with a well-established originator brand that both they and the patient may have come to trust. To encourage more switching to biosimilars, more evidence is going to be the tool for that, said E. Randolph “Randy” Broun, MD, a blood and marrow transplant specialist with Oncology Hematology Care (OHC), of Cincinnati, Ohio.

“I think data are really lacking in this area. Physicians are going to want data to understand that these truly are biosimilars that are interchangeable and they’re not shortchanging their patients by doing this, even under pressure from payers,” he said.

There’s an important distinction to be made, he said. At his practice, at least, biosimilars are a concept that physicians are very familiar with and they now use these agents in many settings and are comfortable with them. But their confidence in biosimilars can be strained when multiple versions of a single reference product start to appear and they are tasked with making the right choices for their patients.

“Once we have 8 different Herceptins (trastuzumab), are they all the same? Is it reasonable to simply pull a different one off the shelf for a patient who got something different 3 months ago? That will be a barrier, I believe. And you’re only going to solve that with a lot of data that are very convincing that these things are perfectly interchangeable,” Broun said.

Cardinal Health has recognized the value in using biosimilars, as their discounts, particularly when many are available on the market, can be significant, and became proactive with its participating physician practices to cultivate an understanding of these agents that would translate into greater use, according to Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars for Cardinal Health.

Parsad said the same goes for her institution. “We took a very purposeful approach to meeting with physicians and nursing staff to talk about the regulatory requirements for approval and demonstrate how biosimilars are similar to reference products, how they have a high standard for safety and quality,” she said.

When it approves a biosimilar, the FDA certifies that it is as safe and effective as the original biologic, and that it has been rigorously evaluated, but the FDA doesn’t give it automatic interchangeable status, meaning pharmacists would be free to substitute the biosimilar with a reference product without informing the physician. Additional requirements are needed for that. It has been hard to explain to physicians that that shouldn’t stop them from prescribing biosimilars, Parsad said. “We felt that was a bit of a bump for us. This is what I’ve heard as well with other colleagues around the country, that physicians do prefer that they are informed when there is a decision whether we should switch or not from the reference product to the biosimilar. But I feel like it went fairly smoothly once there was this very open dialogue.”

It was more of a challenge to develop policies about switching from reference products to biosimilars and in what instances this should occur, she said. A lot of issues arose, such as whether patients should be asked for fresh consent before they are prescribed a biosimilar after having been on a reference product, and if a patient’s condition is stable on a reference product, is it really wise to “rock the boat” and prescribe a biosimilar? And further, following a new diagnosis of metastatic disease, should patients be started on a biosimilar instead of the reference product?

“We had to really work through this saying this is something that we believe as an organization. We believe in the literature, we believe in the data, and we would like to move forward. So, we’ve gotten past that hump,” Parsad said. 

All that said, UCM still wants to see more real-world evidence that shows biosimilars can stand the test of time outside of clinical trials performed in limited numbers of patients for the purposes of FDA approval, she said.

Oskouei agreed. “The conversation has definitely evolved with a desire for more real world evidence and studies around biosimilar to biosimilar switching. With 5 trastuzumab biosimilars on the market now for example, and more in the pipeline, this dynamic is becoming something that providers must navigate.”

At OHC, providers are now using biosimilars in practically 100% of situations when it comes to trastuzumab, rituximab, and supportive care products, such as growth factors for the control of neutropenia in patients treated with chemotherapy products, Broun said. But the practice has found it more manageable to administer a single brand of biosimilar overall except in instances where payers demand something different. “Actually, the ones that give us the most trouble as far as the payers are concerned are the growth factors. Every insurance company seems to have their favorite [pegfilgrastim], and so we stock 3 or 4 of those and we have to sort of interchange them.” 

It would be nice if payers were more lenient about the choice of biosimilars, panelists said. For example, Parsad noted that the administrative work that goes into payer authorizations could be used on something more beneficial, such as patient education and support. “We’re dealing with it as best we can, but it’s unfortunate,” she said.

These issues resemble growing pains for a relatively new option in medicine that is already proving its value, said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center in Louisiana, who served as panel moderator. “The US market is still in its infancy. We just need to let it mature. Biosimilars have been, at least for our organization, a great way to help provide some cost savings to the system and to the patient.”

Next-stage biosimlar acceptance will stand on the strength and availability of real-world data as more of these biologics are launched, a Community Oncology Alliance (COA) conference panel said.

COA Panel Says Confidence Rests on Real-World Data

Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

Here are the top 5 biosimilar articles for the week of April 5, 2021.

Number 5: Seeking to develop a biosimilar portfolio, Stada Arzneimittel has 

Number 4: The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a 

 for a subcutaneous (SC) infliximab biosimilar candidate from Celltrion.

Number 3: India has tightened up guidelines for biosimilar development in a 

 standards equivalent to those in Europe and the United States.

Number 2: Shanghai Henlius Biotech began as a 2-person enterprise in 2010 and now has multiple oncology products in development and 3 biosimilars on the market. An executive discusses its 

Number 1: Sarfaraz K. Niazi, PhD, a member of The Center for Biosimilars® Advisory Board, 

 with a young clinician over the reliability of biosimilarity testing.

To read all of these articles and more, visit 

Videos

The Top 5 Biosimilar Articles for the Week of April 5

Are we there yet with biosimilars? That’s often the back-seat perspective, but this negativism is really based on “fiction” and biosimilars are rapidly gaining ground, according to Ted Okon, MBA, executive director of the Community Oncology Alliance, which advocates on behalf of community-based, nonhospital oncology clinics.

Misconceptions about biosimilars are numerous, Okon said, listing them at the recent Festival of Biologics 2021 biosimilars conference:

Physicians won’t prescribe them because they’re not as efficacious as originator products or the doctors make more money on the most expensive products

Biosimilar naming suffixes and CMS coding for them are stifling growth

Biologics are “natural monopolies” that shut out biosimilars

There have been repeated calls from the Drug Pricing Lab at Memorial Sloan Kettering Cancer Center in New York to regulate the prices of originator drugs rather than trying to make biosimilar competition do the work of trimming the soaring costs of biologics, but Okon said there’s no justification for even considering throwing in the towel on biosimilars. “I think this is just not based in fact, it’s not workable, and it’s complete fiction,” he said.

Peter Bach, MD, MAPP, and Mark R. Trusheim, MSc, 

 requiring “that biologic drug manufacturers lower their prices to affordable yet still profitable levels when their market exclusivity expires.”

Okon in his talk said that proposed policy was “price fixing” under a disguise. “I just want to say that price fixing has never worked in the long-term history of humanity,” Okon said.

Such theories and “fictions” about biosimilars distract from the true facts of the case, Okon said. “The biosimilar market is growing. Yes, it’s taking a while, but it’s growing.” Although the United States is behind Europe in terms of biosimilars approved and launched, the FDA continues to add more approvals each year—29 since 2014—and 73 additional biosimilar candidates are in clinical trials and/or under FDA review, Okon said.

Physicians continue to prescribe more biosimilars, and price competition is improving. “At COA we have a biosimilars committee, and they are committed to the growth of biosimilars. There is price competition and the market could be stronger and produce more savings,” he said.

Hospital Incentives Undermine Biosimilar Progress

However, one place that biosimilars could be absorbed and appear to be snubbed instead is in the hospital community, where financial incentives are heavily weighted in favor of biologic reference products, which means biosimilars in many cases are not even considered, Okon said. He quoted from a January 2021 report from Bernstein, the financial advisory firm, which used a recent federal drug price disclosure mandate to probe what insurers are paying hospitals for the use of reference biologics.

For example, UT Southwestern Medical Center receives $17,241 from Cigna for administering a dose of the Neulasta originator brand of pegfilgrastim, whereas Aetna pays UT Southwestern $6474 per dose. Humana pays Wake Forest Baptist Medical Center $4370 for a dose of the Prolia originator brand of denosumab, whereas United Healthcare pays Wake Forest $2209, according to the Bernstein report. As these data show, because compensation levels can sometimes be high, 30% to 43% of hospitals only carry the innovator products, Okon said 

Okon said the average markups over average selling prices on biologics are 250% although the markups are often much higher, as indicated by the Bernstein information, especially if the drugs are acquired through the 340B drug price subsidy program, which is intended to improve access to drugs for patients. Providing a scenario, Okon said it’s possible for a hospital to be paid almost $8000 for a drug whose wholesale cost is $4500, with the payer being charged over $8000 and the patient paying over $2000 out of pocket.

“You can see, especially with 340B, it makes drugs very, very economically attractive, and as a result, biosimilars are not attractive to use.”

Citing information from IQVIA, Okon said the US market for biosimilars stands at $4 billion annually. Okon called that “amazing growth.”

Growth trajectories for filgrastim biosimilars have been slow but market share growth curves for more recent biosimilars for other products, including bevacizumab, trastuzumab, epoetin, and rituximab, have been very steep, Okon noted. Similarly, price declines due to biosimilar competition are becoming steeper, too.

“It’s very, very interesting. It just took more competition,” he said.

There are culprits holding back the growth of biosimilars, he added. These include patent battles and restrictive deals that favor innovator products. Pharmacy benefit managers and payers are responsible for the latter, he said.

Although there are problems that prevent biosimilars from getting to patients, the following actions could help to improve access and lower prices, Okon said:

Prioritize and streamline the FDA approval process for biosimilars

Eliminate rebate waivers for biologics, including biosimilars

Provide 340B drug discounts to patients, not hospitals

“The bottom line is this: the biosimilar market in the United States is growing and it’s producing savings,” Okon said. “Could it be growing more? Yes. Could it be growing faster? Yes. Could it be producing more savings? Yes. But the solution is not price regulating the market. That will destroy not only the biosimilars but also the biologics market.”

Calls for price regulation and lopsided incentives are threats to biosimilar progress, Community Oncology Alliance (COA) Executive Director Ted Okon argues.

COA's Okon Takes Aim at Biosimilar Misconceptions

 I'm Tony Hagen, senior editor for The Center for Biosimilars®. In a recent white paper, Richard G. Frank, PhD, of the Department of Health Care Policy at Harvard Medical School, and other authors wrote about the access problems faced by biosimilars in the United States market and how certain frictions are preventing these agents from getting to market. But they also found that as more biosimilars enter the marketplace, the prices for biologics are definitely coming down by significant increments. We spoke to Dr Richard G. Frank and Meaghan Rose Smith, the executive director of the Biosimilars Forum, which is a trade group for biosimilars manufacturers.

So, to start off with you, Dr Frank, you have written that originator biologics each have cumulative sales of $40 billion and been on the market for 17 years on average. What does this say about competition in the biologics sphere and the prices that Americans are paying for their medicine?

 Well, I think that because the regulatory structure of governing biologics is different than it is for small molecules, the way that we've promoted competition and the small molecule side doesn't translate directly. What I think has happened as a consequence is 2 things. There are legitimate reasons why the regulatory differences exist but what's happened is, (1) they've been a little bit sticky in terms of adapting to the biosimilar world, and (2) there has been industry behavior aimed at protecting exclusivity protections, both in terms of the regulatory context but also in the patent context that has gotten in the way of biosimilars being able to relatively frictionlessly enter the market.

CfB:Meaghan, do you have any thoughts there?

 Sure, I think that's all correct. Biosimilars are different than generics and there is a different regulatory structure, but the cost savings that they provide can be as important when you look at the increase in drug spending. That's all coming from the originator biologics, so making sure that we're able to access the cost savings from biosimilars is really going to be important. As Dr Frank's paper showed, when there's more competition, there's more savings. So, it's very critical that we find a way to increase that competition.

CfB:Dr Frank, can you explain some of the policy actions that are hindering biosimilar acceptance? You've referred to interchangeability, drug naming conventions, and CMS policy on separate codes and prices.

 Yeah, there's also patent policy that matters here. I think there's antitrust issues here that are potentially at play as well. I could just go down the list for you.

CfB:OK, do you want to hit some of the highlights you feel the strongest contenders should not be?

Well, the easier ones are, for example, changing the naming conventions. I think that would be helpful. We don't know exactly how helpful, but I think they would move the ball a step toward both doctors and patients not exaggerating differences between biosimilars and the originators. I think the development of a better process and a better understanding of how to get to interchangeability will be very important because that concept of interchangeability is what has really driven the success of the Hatch-Waxman Act in achieving the savings that (generics) have achieved. So, I think there is probably a lot more that could be done to advance the potential for interchangeability. Third, on the antitrust side, this is not a settled law yet, but I think we need to really understand bundled contracts and how they can be used to get in the way of entry and demand for biosimilars. Those would be my top 3 right now.

CfB:Okay. Meaghan, did you want to chime in there?

 Sure. Particularly on interchangeability, that's going to be more of an issue potentially in a few years in the [Medicare] Part D space. That's an area where I think misinformation has led to some confusion, where that's not necessary in Part B for physicians to be making the switch to a biosimilar. Physicians always have the freedom to prescribe whatever drug they believe is appropriate for their patients. But that difference has led to confusion and I think some have taken advantage of that. And I know the FDA and FTC have been working together to try and fight some of that misinformation and some of these anticompetitive practices that have really held back biosimilars getting to patients. And in terms of policies, in addition to what you've mentioned, the Forum has really pushed toward right sizing those incentives that we think are currently backwards and making sure that particularly when a physician feels that a switch may be necessary, they have the proper incentives or have no incentive holding them back from doing that.

 If you don't mind, I'd like to sort of tie this into…how you build confidence in physicians when they prescribe [biosimilars]. And while I think that Meaghan was completely right that interchangeability is going to be especially important on the Part D side. On the [Medicare] Part B side, it's important potentially because the data that I'm examining right now show that take-up is driven heavily by the arrival of new patients—this reluctance to switch. I think that if there was interchangeability designated, that would give a great deal of confidence to physicians that they could switch safely. For that reason, even though the primary benefit is this long-term Part D type of benefit, there would be a significant short-term impact because of that extra confidence.

CfB:Let me jump in there with a question on interchangeability. So far, we have no interchangeable biosimilars. Meaghan, have you heard much scuttlebutt in the Biosimilars Forum about the prospects for an application or a modified application for an interchangeable biosimilar in the near future?

 I would look at some of the markets outside the United States to watch closely what's happening there. So, number 1, I'm not aware of any potential interchangeable designation coming in the United States. That's point number 1. And then point number 2 is that [interchangeability] could also be another potential anticompetitive loophole or blockade from an originator brand that they put in front of other competitive products.

CfB:Do you mean that they come up with ways to demonstrate, perhaps in a courtroom setting, that a biosimilar does not qualify on a parallel scale with an originator product?

 I was talking more about if they were then to develop an interchangeable biosimilar of their own.

CfB:Dr Frank, in your study, you mentioned that with few market entrants, the price decreases that many have hoped for from biosimilars are really quite modest, maybe on the order of 5% increments. Can you explain that a little bit and perhaps give us your thoughts on which way you think this is going?

 Just to clarify, we presented a range of estimates: 5% of the low side and 10% of the high side. So, it's somewhere between 5% and 10% for every extra biosimilar comes in. We evaluated that, too. So, if you go from 2 to 3, you get somewhere between the 5% and 10% reduction price. If you go from 2 to 4, you get somewhere between 10% and 20%. I think those are modest by small molecule standards and generics. But, in a sense, you have a line of argument that also says that there's no hope here and that what you want is a public utility regulation model. I think what our results suggest is that it's probably premature to give up on the market. In fact, there are indications that from these early adventures, in a sense, that there are some meaningful reductions in prices, as you crank up competition.

CfB:Meaghan, do you have any thoughts on that? Are we seeing meaningful decreases from the biosimilar sector?

 "Early adventures" in Biosimilarland? I do think it's still an emerging market. When you compare it to where we were, in the generic landscape, 11 years after the Hatch-Waxman Act and we're at the 11th anniversary of the ACA [Affordable Care Act] and the BPCIA [Biologics Price Competition and Innovation Act], it's still a young, emerging market. Number 1, there's clear room to grow and [there are] things we need to do to enhance that growth. There should be more competition and there should be more market share for biosimilars. Patients should have more access. So, this is not where we want it to be, but there are signs that are in the [white] paper that competition is lowering prices, even for patients who are on the originator brand biologic therapy. More competition equals more price reductions. We don't want just 1 biosimilar competing against the reference biologic. We want lots of biosimilars out there competing and giving patients options and bringing down prices.

 Yeah, I think the historical point that Meaghan made is really important because if you think about the Hatch-Waxman Act, there were modest effects early on. But the really big ones that we think about, the ones that save trillions of dollars, really didn't start until the mid- to late-1990s. I think about 1997 to 1999 as being like banner years where you saw huge impacts. It's really at that point that things took off and we're not there yet in terms of biosimilars. And biosimilars, just science wise and regulatory wise, are just harder [to make]. And so, I think that, again, it's premature. The other thing that I think is very important, another point that Meaghan made was that unlike small molecules, what you see is pretty big input originator price responses to entry by biosimilars. Whereas, in fact, you saw the opposite generally in the small molecule space, which is where they raised the prices rather than lowered the prices.

CfB:We've heard recently that there's this concern that the originator companies anticipate the arrival of biosimilars by increasing their prices. So, years before a biosimilar actually steps into the market, an originator has begun increasing its price, sometimes by dramatic steps. AbbVie's Humira [adalimumab] is a strong example, with 7%, 8%, and 9% annual increases. This sets the bar higher. When a biosimilar steps in the market, it can offer a discount, but that discount has much more leeway to come in at a higher level than [the biosimilar company] may have anticipated before. Do you have thoughts on this phenomenon?

 Well, I'm not sure I buy the story entirely because if you look at lots and lots of drugs where there is no biosimilar threat at all, you see pretty significant price increases. In fact, that's one of the targets of public policy, is that the price increases are going up without any new information about efficacy or any big change in market conditions, including inflation, to justify them. So, I'm not sure I buy it even though I think the point you're making about creating more room for biosimilars to enter profitably is probably the case.

 I know there are a number of lower cost biosimilar products planned for entry to compete with Humira, and that's the number 1 selling biologic and there have been a number of games to delay entry of those biosimilar products. Along with what Richard was saying, I can't say if the reason for the price increases was because of planned biosimilar competition or for other reasons but I think it does point to the severe need for competition to lower those prices.

CfB:It'll be very interesting to see what happens in 2023. We have at least 6 adalimumab biosimilars coming onto the market. Whereas, up until now, we've seen biosimilars come in 1 at a time. So, what happens to the pricing levels at that point will be very, very interesting to see.

 Sure, and as we've talked about with the number of products and increased competition, that will be really interesting.

CfB:Contracts and rebate practices are identified as an issue in the report. Biosimilar companies also rely on these practices. Meaghan, could you comment on this aspect of marketing and the heavy reliance on these deals to acquire market share?

 Sure. So, I know this is something that the FDA has pointed out as a potential anticompetitive practice. The FDA and [Federal Trade Commission] have held a workshop on it as an issue. There are some anticompetitive practices that are blocking patient access to some lower cost products. Some of these practices we've talked about needing to fix like fail first [step therapy], which doesn't necessarily make sense. You have to fail first on the reference product before you can have the biosimilar and it's clear that, just from a patient perspective, it's not going to work. That's certainly something that we're taking a look at.

 I think the issue here is using a portfolio of rebates as leverage for exclusionary practices is a key thing. What Meaghan pointed to is an exclusionary practice, which is these fail first policies, which, in a sense, take the concept of fail first and stand it on its head. Typically, the reason we had fail first was to get people to adopt generics quicker, and only if they failed on the generic would they get to the brand drug. This does the opposite and serves essentially to exclude use of biosimilars. The economics are starting to be worked out on this. The antitrust law has not yet been sorted out on this, but I think that is coming. There are cases, including the one around Remicade [infliximab], where this is a fundamental issue. I think we're going to see some clarification on the antitrust law and the antitrust economics over the next couple of years as these things are sorted out.

CfB:Now, Remicade is an example of a reference product where you've seen the least decline in prices yet.

 Although, if you see the picture in our report, it's actually accelerated recently. What's interesting is that most of the decline in price has come because the originator dropped its price because they've held on to a very large share of the market. So, even at the end of that, they're still holding I think north of 90% of the market, which cushions their price declines a little bit because they do hang on to things and the prices are still at a pretty high level.

 Yes, and that's the case where the biosimilar has ended up benefiting patients due to decreasing the costs for patients overall. One of the biosimilars launched at a 35% lower price than Remicade and still the market share is quite low, as you pointed out.

CfB:What's to account for that lack of movement in the originator price, and the change in market share do you think, Meaghan.

 So, I think there are a couple issues that we talked about. One is some of the contracting practices that are an issue. There's also an issue with provider behavior for different disease states that Richard referred to where a lot of the biosimilar uptake is taken up by new patients. If you look at some of the differences between the oncology products and the oncology disease state, compared with some of the other reference products where providers and patients are managing a chronic condition, patients are on an oncology product for a shorter time. So, physicians are not battling the switch issue like they are with a Remicade product. That's why for some of these more chronic diseases, the provider incentives are so critical. Where biosimilars are having more success, it's because physicians are, frankly, having an easier time prescribing the biosimilar because there's less resistance.

CfB:What are your key takeaways from the report and the current landscape for biosimilars? Meaghan, would you like to go first?

 Sure. Thank you, Tony. I think this was another piece of evidence and another analysis that shows how biosimilar competition can benefit patients with decreasing prices and lowering health care costs and that more competition equals increased health care savings. That's an area where we're going to be focused on trying to increase health care savings and lowering health care costs with more competition.

 I think this study contributes to the conversation that's going on about how much potential there is for competition in this market. Second of all, to the extent that the experience with biosimilars is different from that of [generics and the] Hatch-Waxman Act, which is, in a sense, the model for the BPCIA, what [potentially] accounts for that? I think the evidence that we've put together, so far, is (1) there's potential here for the market and we have to give it some time to evolve along the lines that Meaghan pointed out. The second thing is that there are clearly impediments to entry. Even after you've met all the standards for approval, there are still impediments to even getting into the market. I think those need to be addressed in regulation and potentially other competitive practices on the payer and antitrust side. I think those are, in a sense, where we think the state of play is right now.

Richard G. Frank, PhD, and Meaghan Rose Smith discuss a recent white paper on the regulatory and anticompetitive impediments to biosimilar market entry and the hope for biosimilar savings.

Dr Richard Frank and Meaghan Rose Smith Discuss “Friction” in the Biosimilar Market

An Ontario, Canada, biotech company that uses tobacco plants to cultivate antibodies for biosimilar production 

 of a biosimilar pembrolizumab for the Brazilian market. Pembrolizumab (Keytruda) is a “programmed death” (PD) inhibitor that counteracts tumor cells’ ability to deactivate the immune system response to malignant cells. It is used in the treatment of melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, and stomach cancer.

PlantForm uses tobacco plants rather than animal cells to develop antibodies for use in biologics production. Antibody genes are merged with plant bacteria to “infect” the tobacco plants and cause them to produce antibodies, a process that takes about 10 days, according to company information. The company touts this as a way to avoid some of the complexities of standard production techniques that use animals and bioreactors.

PlantForm is partnering with PlantPraxis Biotecnologia and Bio-Manguinhos/Fiocruz to create the pembrolizumab biosimilar. Merck is expected to lose patent exclusivity protection for Keytruda in the United States, European Union, and Brazil in 2028, allowing a potential entry point for biosimilars. “We want to make a difference in this market by transferring an innovative technology that will bring a low cost biosimilar pembrolizumab to Brazil,” said Germana Regazzi, director of PlantPraxis.

PlantPraxis is a joint venture between PlantForm do, which is a subsidiary of PlantForm, and Axis Biotech Brazil. Bio-Manguinhos is a division of the Brazilian Ministry of Health that furthers the development of technology and production of vaccines, among other activities.

According to PlantPraxis, the pembrolizumab market is expected to reach $25 billion by 2025, making it a potentially lucrative target for biosimilar competitors. PlantPraxis is not alone in cultivating ambitions for participation in this market. 

of Sydney, Australia, announced in September 2020 that it is working to develop biosimilars for pembrolizumab and nivolumab (Opdivo), another PD inhibitor.

PlantForm has other biosimilars in development, including versions of trastuzumab and ranibizumab, which treat forms of cancer and macular degeneration, respectively.

For further reading about the development of PD inhibitor biosimilars, click 

PlantForm will use tobacco plants to develop antibodies for its checkpoint inhibitor pembrolizumab biosimilar.  

PlantForm Will Challenge Merck's Dominance for Pembrolizumab

Shanghai Henlius Biotech is one of many companies in China working to crack open the market there to biosimilar competition. However, Henlius stands out so far for some notable achievements, such as bringing the first biosimilar (rituximab) to market in China and achieving significantly rapid market penetration in the product's first several months of life. 

The company has bigger ambitions to achieve dominance not only in China but also on the world biosimilar stage, Ping Cao, company vice president of business development, explained at the recent Festival of Biologics USA meeting. 

Henlius was formed in 2010 and filed its first biosimilar investigational new drug application (HLX01, rituximab) with the Chinese National Medical Products Administration (NMPA) in 2011. The company opened its first Good Manufacturing Practices–certified factory in 2016, and HLX01 was approved in China in 2019, becoming the first biosimilar approved in China.

In July 2020, the company saw its trastuzumab biosimilar (HLX02, Zercepac) approved in the European Union. The same drug was approved a month later in China, and in December of 2020, Henlius succeeded in getting an adalimumab biosimilar (HLX03) approved in China, also.

The company decided that its first several biosimilars would be oncology products because of the relatively huge market for oncology treatment in China. That meant the company saw huge potential in rituximab, trastuzumab, and bevacizumab biosimilars. The company anticipates an FDA filing for its bevacizumab biosimilar (HLX04) in 2021.

It also anticipated strong growth for its adalimumab biosimilar, referencing the blockbuster Humira, which Cao said still has a relatively small share of the market for autoimmune diseases in China. “Autoimmune disease actually has a huge unmet need in China,” she said. Humira’s 2019 sales share in China vs its global penetration rate was 0.2%, and the estimated access rate (to adalimumab) in China in 2020 was 1.3% of patients vs a potential market of 6.7 million patients.

Global marketing of its biosimilars is an important element of the company’s growth strategy , but Henlius also wants to develop biobetters, drugs that are based on originator products but deliver better efficacy, improved safety, or other enhancements. Developing new biologics and combination therapies also is a targeted area for growth at Henlius, Cao said. 

Its second wave of biosimilar contenders may target the cetuximab (Erbitux, rectal and head and neck cancer), ramucirumab (Cyramza, solid tumors), pertuzumab (Perjeta, breast cancer), and denosumab (Prolia/Xgeva, bone loss) markets. Henlius has biosimilars of these drugs in phase 1 development currently.

The company is seeking a rheumatoid arthritis indication for its rituximab biosimilar and, if successful, this indication would make HLX01 a bio-innovative medicine because the reference product, MabThera, has not yet been approved for this indication, Cao said. China’s NMPA has accepted a new drug application for HLX01.

Under its current indications, HLX01 was a record breaker, taking 50% of market share for new patients treated within 5 months of launch in China and surpassing market share of the originator product, MabThera, after 14 months on market, Cao said.

Although the cetuximab product candidate remains in early stage trials, Henlius has already granted commercialization rights in China to Shanghai Jingze. The company has multiple nonbiosimilar product candidates in early-stage development and antibody drug combinations in mid- to late-stage development for cancer treatment.

HLX02 (trastuzumab) was the first China-made biosimilar to gain approval in Europe, Cao said. “It has been launched in the United Kingdom, Germany, Portugal, and Spain, and used in tier 1 hospitals of Europe,” she said.

Henlius is working to increase the scale of its manufacturing operations to support its global ambitions for sales growth. It has 2 plants currently: one in Xuhui and a second in Songjian, with a total installed production capacity of 44,000 L. Both of these factories were fitted out and made operational within the past 3 years.

In Sonjiang, Henlius has a third plant in development, which Cao said when complete would rank among the largest biologics production facilities in Asia for size. This plant following phase 1 of development would have 36,000 L of production capacity, which would be increased to 45,000 L later on. Henlius currently has a manufacturing staff of 758 employees, Cao said. “For biologics, the important thing is to reduce manufacturing costs. We have our own proprietary technology to enable this mission.”

The company has its own sales team in China and is looking for partners in the rest of the world. The China sales team numbered 400 full-time employees at the close of 2020 and is projected to reach 1000 full-time workers by the end of 2021. Henlius has established relationships with 2700 upper grade hospitals and 30,000 oncologists in China, Cao said.

Shanghai Henlius Biotech began as a 2-person enterprise in 2010 and now has multiple oncology products in development and 3 biosimilars on the market. An executive discusses its business trajectory.

Shanghai Henlius Biotech Maps Out Its Biosimilars Future

The story of biologics and biologic copy products in India is very much a story about a work in progress. Although some companies are producing genuine biosimilars on par with international standards, many products fall into categories that are not comparable to biosimilar quality in the West. Recently, Indian regulators have endeavored to provide a pathway toward biosimilar development that meets international standards.

Newer, more comprehensive guidelines issued by Indian authorities in 2016 were intended as an upgrade to standards from 2012 that governed 

, India’s term for biosimilars. “A similar biologic product [in India] is that which is similar in terms of quality, safety, and efficacy to an approved reference biological product based on comparability,” the authors of a recent paper explained.

The authors noted India’s success in providing access to biologics, stating that approximately 60 biologics have been approved in India, almost half of which are similar biologics. In India, the cost of similar biologics “is approximately half the cost of innovator products,” and patient assistance programs address affordability and improve access.

However, there is also the potential for compromise: almost 20 similar biologics to infliximab, etanercept, adalimumab and rituximab were approved based on the less-stringent 2012 guidelines and were supported by limited clinical data.

The authors discuss the difficulty of producing biologics and true copies of originator products in a country that does not have the resources that the West does. “It remains a big challenge for a biosimilar manufacturing company to develop a similar product, as detailed information on the process of manufacturing of the original drug is patent protected and also because the same cell line is not available to the biosimilar manufacturer. Any changes in the manufacturing process such as use of different cell lines, growth medium, and protein purification processes can also result in variations in the final product,” the authors wrote.

Further, doubts about the quality of biologics persist and small patient population sizes during trials conducted to demonstrate bioequivalence to reference products may not produce the volume of data necessary to satisfy the need for statistical clarity, the authors wrote.

“In controlled clinical studies of biologics, particularly biosimilars, safety concerns may occur beyond the study completion. Long-term evaluations, such as postmarketing studies of biological agents, are required as there are only limited patient experiences available during approval in terms of safety and immunogenicity. Side effects related to the long-term use, off-label use, drug-drug interactions, or use in comorbid conditions can only be identified on exposure to the drug after its approval,” they said.

, need to be distinguished from similar biologics to prevent physician and patient confusion. They cite significant differences in the approval process for these products. Unlike similar biologics, intended copies do not undergo comparative clinical studies or analytical studies to demonstrate similarity to the reference product and have not been equated with similar biologics under the 2016 regulatory guidelines. With so little data, patients “face a greater risk of therapeutic failure and side effects” from these products, the authors reasoned.

Similar biologic products were evaluated on a case-by-case basis prior to the first approval guidelines for similar biologics released by India’s Central Drugs Standard Control Organization (CDSCO) in 2012. The 2016 guidelines were developed with some input from the World Health Organization (WHO) and “expert consensus opinion.” The goal of the 2016 rules was “to provide a well-defined pathway at par with international regulations,” although there is lingering controversy over whether India’s current guidelines achieve international standards.

The authors compared CDSCO’s 2016 guidelines with those of the FDA, the European Medicines Agency (EMA), and the WHO. Like the guidelines from the FDA, the EMA, and the WHO, India’s require demonstration of similarity to the originator product in nonclinical studies, a comparative pharmacokinetic and pharmacodynamic study in humans, a comparative clinical efficacy and safety trial in a relevant medical condition (India’s guidelines specify the trial should include more than 100 patients), and postmarketing safety monitoring.

The authors also highlighted “key considerations” regarding the current guidelines, which they say should be addressed in future iterations.

Interchangeability is not addressed in India’s biosimilar guidelines, and the authors noted that reference products are often switched for similar products “randomly by the prescriber or pharmacist based on the product cost and assumed patient affordability.” In 

, interchangeability is determined by individual member states. The United States has a process for biosimilar products to demonstrate 

, but no biosimilar has yet met this standard.

Nomenclature is also not addressed in CDSCO’s 2016 guidelines. The authors commented that accurate safety monitoring of biologics and biosimilars depends on identifiability “with easily distinguishable product names.” The WHO recommends a 4-letter suffix with the international nonproprietary name to distinguish a biosimilar from its reference product and other biosimilars to that reference product. However, 

 have been controversial, as they are thought to cause patient hesitance or confusion.

The authors also expressed concern about transparency in labeling, saying the package insert for a similar biologic should clearly disclose the extent of similarity to the reference product with respect to safety, immunogenicity, and efficacy.

Overall, the researchers view the 2016 regulations as successful in improving “stringency” in the approval process and more closely matching the safety requirements of international guidelines. However, some experts consider the 2016 requirements less stringent than EU and US standards.

Jois R, Mukherjee S, Rajeswari S, Rath PD, Goyal V, Gupta D. Similar biologics in India: a story of access or potential for compromise? 

. 2020;152(5):456-467. doi:10.4103/ijmr.IJMR_43_18

India has tightened up guidelines for biosimilar development in a quest to achieve standards equivalent to those in Europe and the United States. 