Articles

The United States has missed out on almost $20 billion in savings as a result of not having a competitive biosimilar market, according to findings from the Pacific Research Institute.

Report: Lack of Biosimilar Competition Contributed to Billions in Lost Savings

Breast cancer specialist Hope S. Rugo, MD, FASCO, an advisory board member for The Center for Biosimilars®, has been at the forefront of groundbreaking oncology advancements. 

Rugo Wins Prestigious Giants of Cancer Care® Award

Lotus and CKD Pharmaceutical intend to be among the first to bring a darbepoetin alpha biosimilar to Southeast Asia.

Lotus Inks Deal With CKD to Distribute Darbepoetin Alpha Biosimilar

We sat down with Representative Glenn Grothman (R-Wisconsin), the author of HR 8190, a bill that would waive interchangeability requirements for biosimilar insulins, to discuss why this bill is needed for Americans and what it could mean for future biosimilar legislation.

Not So Different: Rep Grothman on His Bill to Make Biosimilar Insulins Interchangeable

Isha Bangia, PharmD, MBA, is a manager of US market access at Certara Evidence & Access. She received her PharmD from Rutgers University and an MBA from Johns Hopkins University. Her current responsibilities include optimizing product value stories and working with customers to improve access across the US healthcare system. Her experience includes practicing pharmacy, payer market research, and pharma strategy and analytics. Her work has covered many therapeutic areas, including biosimilars, oncology, diabetes, vaccines, and rare diseases.

Amgen's Onpro autoinjector device for pegfilgrastim is a stunning example of how product differentiation via drug delivery devices can protect market share in the biologics market.

Contributor: Drug Delivery Devices Help Originator Companies Retain Market Share

Comparative biosimilar efficacy trials are unnecessary to demonstrate that drug candidates are equivalent to reference products (RPs), authors of an analysis argue in a new paper. The group from the UK’s Medicines and Healthcare Products Regulatory Agency contends that, except in extreme cases, analytical testing and a pharmacokinetic trial are sufficient to demonstrate biosimilarity.

They propose a streamlined approval process for biosimilars to accelerate patient access, in which “efficacy trials are reserved for exceptional circumstances.” 

“Little Additional Evidence of Biosimilarity”

The approval processes for biosimilars in the United States and Europe do require extensive analytical testing to determine similarity, followed by in-human pharmacokinetic (PK) and pharmacodynamic investigatory studies and efficacy, safety, and immunogenicity trials. However, “the discriminatory power of these studies decreases in this order,” the authors contend.

“In 2020, it is increasingly questioned whether clinical efficacy trials of biosimilars are still necessary. Revisiting the requirement for efficacy trials appears timely because significant technological advances have been made over the past 10 years and considerable scientific and regulatory experience has been accrued since the first biosimilar was licensed in 2006,” they wrote in a prepublication draft for 

The authors note limitations of comparative efficacy trials, such as limited statistical power to detect small treatment effects or differences in safety and immunogenicity. They said that to detect all clinically relevant differences between biosimilar and originator, “up to a few thousand” patients would be required, whereas most comparative efficacy studies for approved biosimilars have enrolled between 350 and 900 patients. Enrolling sufficient numbers of patients is especially challenging for orphan drug or pediatric indication trials, which the authors said leads to underpowered studies and difficulty drawing conclusions.

In addition to these limitations, the authors argue that clinically meaningful differences in efficacy, safety, or immunogenicity between a biosimilar candidate and its RP “would be unlikely once analytical and PK comparability has been shown.” Therefore, they claim that comparative efficacy trials are “neither an effective discriminating tool for the comparison between biosimilar and RP, nor an efficient use of limited resources.”

To determine whether differences found in comparative efficacy trials changed the course of biosimilar approvals, the authors analyzed 20 complex biosimilars related to 6 reference products approved in the European Union as of the end of 2019. Regarding that analysis, the authors wrote, “we have not found any publicly available results of an efficacy trial being the critical reason for not submitting a marketing authorization application for a biosimilar candidate.” They added that differences detected in clinical trials “did not, on their own, preclude the approval of the biosimilar.”

The authors suggest that in-depth knowledge of “crucial aspects of efficacy, safety, and immunogenicity of the RP that emerged during clinical development” can help predict potential issues with a biosimilar. Additionally, they said that technological advances have allowed analytical tools to detect small, potentially clinically relevant differences between reference products and candidate biosimilars.

They also argue that differences between biosimilar and RP that might affect immunogenicity are better detected via analytical tests, “which are more sensitive than the evaluation of the human immune response because of multiple confounding patient- and disease-related factors.”

Multiple batches of RP are evaluated to establish a baseline range within which the biosimilar candidate must fall as evidence of equivalency. The authors write that the variability of the reference product range “is unlikely to be of clinical relevance” and neither should there be a concern if the biosimilar candidate falls within that range. 

“Therefore, we contend that, in most cases, an efficacy trial is no longer required to establish biosimilarity once comparability has been demonstrated through the analytical and clinical PK studies,” they wrote.

Their proposed approval process would use in-depth understanding of the RP and advanced analytical testing to minimize clinically relevant differences between RP and biosimilar. They acknowledged this would require extensive knowledge of the RP’s mechanism(s) of action; physicochemical and functional properties likely to be clinically relevant; PK, efficacy, safety, and immunogenicity profiles; and impact of antidrug antibodies on pharmacokinetics.

The authors also recommended extensive quality data must be generated for both the reference product and its biosimilar candidates, with analysis of multiple batches of the originator biologic over months to years to take into account manufacturing variability, and comparison of each batch of biosimilar to the reference product.

The authors still consider a confirmatory PK trial necessary for comparing bioavailability between biosimilar and reference product, as the 2 products by definition will not be identical. Importantly, they argue that the PK trial “provides some safety and immunogenicity information from exposure in humans.”

Regarding safety, they said robust pharmacovigilance will be required; however, they reiterated that safety issues not identified via analytical or PK testing are unlikely, saying “more than a decade of clinical experience indicates that a new safety signal solely identified with a biosimilar is extremely unlikely unless there are additional factors unrelated to the active molecule itself (eg, different excipient or device).”

The authors claim this expedited approach to biosimilar approvals “provides a streamlined pathway for expediting approval of biosimilars, thereby promoting wider patient access to these crucial therapies.”

For more recent opinion on FDA biosimilar guidelines, 

Bielsky M, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. 

Much of the groundwork for establishing equivalence is established in the pharmacokinetic evaluation. Further studies add less and less to the body of evidence for biosimilar approval, UK regulators write. 

UK Regulators Contend Biosimilar Efficacy Trials Are Redundant

 trial for its coronavirus disease 2019 (COVID-19) monoclonal antibody treatment (CT-P59), Incheon, Republic of Korea–based Celltrion Healthcare has received approval to initiate a phase 2/3 trial.

“Given that COVID-19 represents a significant global threat to life, there is an urgent need to identify treatments that can help stabilize our response to the pandemic. The initiation of the global phase II/III pivotal trial of CT-P59 is an important step forward,” said Sang Joon Lee, PhD, senior executive vice president at Celltrion, in a statement.

The news comes as Celltrion’s infliximab biosimilar (Remsima) is being tested in the phase 2 

 trial to assess its efficacy in treating patients with inflammation linked to COVID-19 during hospitalization.

The phase 2/3 trial will be a global trial evaluating the safety and efficacy of CT-P59 in patients with mild-to-moderate symptoms related to COVID-19.

Celltrion, primarily a biosimilar developer and manufacturer, said it expects to have primary results for the phase 2 portion of the study by the end of 2020.

The company has filed an investigational new drug application for the trial in 6 countries, including the Republic of Korea, the United States, and Spain.

Celltrion said it plans to enroll more than 1000 patients in the multinational trial. Assuming the phase 2/3 trial yields positive results, the company expects to be able to apply for emergency use authorization.

“Celltrion has begun manufacturing the process validation batch of CT-P59 and plans to increase manufacturing capabilities to meet the current global and domestic demand for the anti-COVID-19 monoclonal antibody treatment candidate,” the company said in a statement.

In addition to the phase 2/3 trial, Celltrion has initiated an ongoing in-human global phase 1 trial for CT-P59 in patients with mild cases of COVID-19. The company said it also plans to investigate whether CT-P59 is effective as a preventive treatment for those who are in close contact with patients with COVID-19.

Celltrion moves another step forward in its bid to get a coronavirus disease 2019 (COVID-19) treatment on the market.

Celltrion's COVID-19 Antibody Treatment Moves Into Phase 2/3 Trial

Number 5: A few recent surveys suggest that physicians in the field of rheumatology would lean toward 

 over injections as a way to improve very high patient nonadherence rates.

 emerging on oncology biosimilars from Mylan, Samsung Bioepis, and Shanghai Henlius Biotechwill be presented at the European Society for Medical Oncology Virtual Congress 2020 this week .

Number 3: Intellectual property law attorneys from the Washington, DC, offices of McDermott Will & Emery LLP, discuss 5 of the 

 in biologics litigation that have emerged in recent months.

Number 2: With anti–tumor necrosis factor (TNF) therapy showing promise in treating coronavirus disease 2019 (COVID-19), authors called for these agents to have a 

Number 1: In the effort to find treatments for coronavirus disease 2019 (COVID-19) and related conditions, Celltrion Healthcare’s monoclonal antibody has shown promise in a 

To read all of these articles and more, visit 

Videos

Here are the top 5 biosimilar articles for the week of September 14, 2020.

The Top 5 Biosimilar Articles for the Week of September 14

Positive pharmacokinetic (PK) equivalency data were presented for PrestigePharma’s trastuzumab biosimilar candidate (HD201, Tuznue), at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

PrestigePharma is a Singapore-based biopharmaceutical company that has an application for HD201 under review with the European Medicines Agency. The company previously reported positive biosimilarity findings for HD201 at ASCO20 Virtual, the annual meeting of the American Society of Clinical Oncology.

In the ESMO data, PrestigePharma reported PK equivalence between HD201 and 2 versions of the reference product sold in the United States (US-Herceptin) and Europe (EU Herceptin), based on findings from a randomized, phase 1 trial (TROIKA-I, NCT03776240). Investigators said 105 healthy male subjects randomized to 3 arms received the biosimilar candidate and reference versions at an intravenous dose of 6 mg/kg for 90 minutes.

The HD201 and Herceptin trastuzumab versions were compared based on primary end points including peak concentration and total drug exposure. PK equivalence for HD201 was considered met if the confidence intervals were within conventional equivalence margins of 80% and 125%. Secondary end points included other PK parameters, safety, tolerability, and immunogenicity. 

Investigators said HD201 demonstrated PK equivalence for all criteria. They said the incidence of adverse events was lower in the HD201 cohort (20%) compared with the EU Herceptin (34.3%) and US-Herceptin (31.4%) groups. The most common adverse events were infusion-related reactions and administration site reactions.

 from TROIKA-I and TROIKA, which involved patients with HER2-positive early stage breast cancer. These earlier results indicated that the biosimilar was safe and well tolerated with PK comparable to Herceptin. In TROIKA, patients received HD201 or EU-Herceptin with chemotherapy in the neoadjuvant setting followed by trastuzumab monotherapy in the adjuvant phase.

The total pathological complete response rate was 46.6% for patients in the HD201 arm versus 46.2% in the Herceptin arm. The overall response rate was 90.8% vs 89.4%, respectively. TROIKA had 574 patents evaluable for response for the ASCO report, and the study remains ongoing (NCT03013504).

HD201 is the lead biosimilar candidate under development at PrestigePharma. The company also has bevacizumab and adalimumab biosimilars in development.

Demarchi M, Coliat P, Chung Shii Hii J, et al. A double-blind, randomized, parallel group study to demonstrate the equivalent pharmacokinetic properties of a single intravenous dose HD201, a trastuzumab biosimilar candidate, versus EU trastuzumab and US trastuzumab. Poster presented at ESMO Virtual Congress 2020; September 17, 2020. Abstract 590P.

Singapore-based PrestigePharma presents fresh equivalency data supporting its case for regulatory approval of HD201.

PrestigePharma Reports Positive PK Data for Bevacizumab Candidate

To watch part 1 of this interview, click 

The Center for Biosimilars® (CfB): Hello, I'm Matthew Gavidia. Today on MJH Life SciencesTM Medical World News, The Center for Biosimilars® is pleased to welcome Wayne Winegarden, PhD, a senior fellow in business and economics at the Pacific Research Institute (PRI), as well as director of PRI's Center for Medical Economics and Innovation.

Providers want freedom to use the same biosimilar each time rather than have to use a different one according to each payer and formulary. Do you see any workable solutions to this problem?

Yeah, absolutely. We're beginning to get into broader health insurance and health care reforms. That is an essential part of how we get to a better health care system, where the patient and the provider need to be in control of that patient's health. And to the extent that the provider is familiar with their patient, they understand what other medicines they're on and they understand the patient's unique circumstances. They're obviously much better positioned to know what the right medicine is and so, they absolutely need to be empowered. And the patient, on the flip side, should have that control because it's their health.

Again, this is getting slightly away from specific biosimilar changes and the interchanges of how we fundamentally improve how our health care system is operating from that patient-centered and provider-centric health care model, which is absolutely incredibly important in terms of broader health care reforms.

CfB: Are there other reforms in the payer paradigm that you think might be workable?

There are. We talked about shared savings, fail first therapies, separate biosimilar tiers, and ASP [average sales price] reform so that you have the same percentage dollar markup across a biologic in a biosimilar. All of these types of reforms, again, [represent] the idea being that you're not disincentivizing or disadvantaging one product over the other.

Along those lines, right now, we have a lot of tie-ins and sales. Those can be anticompetitive, and those should be changed. So, what we really need is a more efficient, less obstructed market so that the competitive pressures can come into play. We already see in the generics market that drug competition is a very effective means for driving down price and improving quality of care and improving adherence, which improves health outcomes. That same process can be leveraged for the biologics market. All of those reforms that we're talking about need to work toward that specific goal.

CfB: You talk about regulatory inefficiencies. Can you discuss broadening the applicability of the interchangeable designation?

Interchangeability is one of those complex issues. And a really interesting issue in terms of biologics when we're talking about interchangeability is that normally it refers to a pharmacist, and typically it's much more relevant for the small molecule drugs. Does a pharmacist have the ability to change a patient from a reference product to a generic product without going back to the physician? You need the interchangeability designation to make that work.

Often when we're talking about a biologic, it's being administered in a clinical setting. Well, in a clinical setting when the doctor is administering it, the doctor can prescribe the medicine that they believe is most appropriate for that patient. So, the interchangeability designation for the most part is not relevant. The provider, the doctor, or whoever is administering the medicine should have the right to use the medicine they feel is best for that patient, taking into account differences in costs. You have just as efficacious medicines, like a biosimilar to the originator, but one's cheaper.

There are clear advantages to the doctor having the ability to do that. And if interchangeability issues are creating confusion or hesitancy about that, they become a regulatory obstruction. So, to the extent that those issues are impacting our use of biosimilars, that is a very troubling regulatory policy

CfB: Semglee, an insulin glargine, was approved as a 505(b)(2) application and deemed to be approved under the BPCIA [Biologics Price Competition and Innovation Act]. [Semglee is therefore not technically a biosimilar]. Biocon Biologics has to apply separately to get a biosimilar and an interchangeable designation. What are your thoughts on this?

Again, we need that clear pathway. And to the extent that we don't have that, that is problematic. One of the things about insulin is that a lot of the affordability issues from insulin are actually coming from how we price drugs systemically, that gross-to-net bubble, where the patient's costs are based on that gross price, or the list price, which has been rising, but, actually, net costs have been going down. So, that's a very important concern when we talk about insulin—fixing that problem so that, in effect, we're improving patient affordability to actually reflect the market trends, not this inflated bubble. But with respect to the biosimilar versions, there are those complexities. I believe we're getting closer to getting that resolved. The quicker we can do that, the better. Again, more competition is always better than less. So, we are making progress in terms of that with some of the changes being implemented. That is certainly favorable. Could it be more efficient? Absolutely and we need to push toward that.

CfB: President Trump has proposed to create foreign drug buying pathways for Americans so they can have access to cheaper drugs, particularly insulin. What's your take on this as it relates to Canada?

It's a terrible idea. It's a terrible idea in relation to Canada, the [United Kingdom], and Europe. It is a bad idea for a number of reasons. First, let's think about Canada and let's think about the practical issues. There's 300 million Americans and there's 37 million Canadians. It's not possible for Canada to be the drugstore for the United States. [This policy would not] address our drug affordability issues.

I think, more importantly, you have access issues in Canada. They have access to about 50% of the medicines that have come out over the last decade and a half or so. We have access to nearly 90% of those medicines, which, by the way, means that if you have drug importation on that 50% of medicines that aren't available, you don't have drug importation. You can't import something that's not available. There are those problems as well.

But you're not importing all of those problems to the extent that you can get [drugs] into the United States; you're just taking the Canadian price controls. If you think price controls are the way to lower costs here, and [they’re] not, we should have the courage to have that debate and do it here or not do it here. The problem with price controls is that you decrease the amount of innovation. So, you harm patients in the future, and you decrease access. All of the problems that you've seen in these other countries, you would import into the United States.

I think, more importantly, there are ways to address drug affordability in the United States that maintain that balance that we get right. We do this better than other countries. We promote affordability and innovation. Look at the small molecule markets: 90% of small molecule drugs purchased over the pharmacy counter are generics. Most of those, about 95%, are going to cost the patient $20 or less. So, we have affordable drugs and we have continued innovation because you have the incentive to cover the $2.6 billion to $2.9 billion it costs to develop a new a new drug or a new biologic. We have that balance struck well on the small molecule side.

With respect to biologics, there are issues we have to talk about, such as biosimilar competition. We have to address the pricing issue in terms of the gross-to-net bubble, where we have an incentive for gross prices to overinflate. It [affects] the competition. You really want competition on the net prices in the market price. That would drive down the cost for the patients, but it would keep the systemic costs where they are. I don't think most people realize that if you look at the growth in net prices over the last 5 to 10 years, it’s actually less than overall medical care inflation. So, the problem is that the drug pricing system that we have is shifting too much of the cost to patients, and that's what needs to be addressed.

I go into that tangent because that's a much more effective way to create drug affordability here in the United States without bringing in all the problems that we would through drug importation, or bringing in price controls. And we haven't even gotten into the issue of counterfeit drugs.

If you open up the US drug markets to importation, you also open exposures to this problem [of counterfeit drugs], which is already a large problem. [Some] 10% of drugs on the market are counterfeit drugs. These are medicines that [may contain] a yellow highway paint, gypsum. Sometimes they'll have a drug that's not supposed to be there or that you could be allergic to. Again, we're opening up the drug supply chain to greater infiltration by counterfeits, and that's dangerous to patients. For all of those reasons, importation just makes no sense.

CfB: British Columbia has noticed significant savings on its mandatory switching since May 2019, and they've been able to plow substantial savings back into health care to improve access. Are there any lessons here that we can learn from?

I think the lessons are biosimilars create systemic savings. These are medicines that are just as efficacious [as reference products] and can lower overall spending. We don't need mandates. Again, this is something that providers need to be in control of along with the patient in that patient-centered proposal. But again, if you have a medicine that's just as efficacious [as the reference product], but is much cheaper, why wouldn't you use it where it's appropriate. And so, I think it demonstrates the real savings that we can generate here by just creating a more competitive market, not to go down that mandating route, but to remove the obstacles that are inhibiting a much more advanced competitive market here in the United States.

CfB: Can you discuss any current biosimilar legislation that you find promising or noteworthy?

What I'm most excited about, more than legislation, is the actual market dynamics that we're seeing. And I think that the growth in share that's occurring in the biosimilars market has been very encouraging. And we're beginning to see that market stand up. We're beginning to see the [effects of] education. People are recognizing the potential savings that biosimilars can offer and how they actually are just as efficacious as the originator product. As that continues to grow and as more companies continue to insist on favorable tiers for biosimilars and favorable terms, it could be very exciting for the future.

CfB: And lastly, as the FDA is busy with COVID-19–related issues, how is that affecting the pace of biosimilar approvals? And does the FDA have the resources it needs to do the job?

All hands being on deck on COVID-19 has consequences. It has consequences across the board. You see that in clinical trials. And so, obviously, the faster we can overcome that, the better. But there are undoubtedly consequences because everything requires resources and there's just a finite amount of resources. Things are still progressing across the board. We're still seeing progress outside of the COVID-19 area, including innovation with drug approvals. All of those haven't come to a complete standstill; but, undoubtedly, the focus, and rightly so, is on addressing COVID-19. So, it is the right thing to do, but as with so many things in the economy and society right now, COVID-19 is front and center.

CfB: To learn more, visit our website at centerforbiosimilars.com. I'm Matthew Gavidia. Thanks for joining us.

Wayne Winegarden, PhD, senior fellow in business and economics at the Pacific Research Institute (PRI) and director of PRI’s Center for Medical Economics and Innovation, discussed why importing drugs may not lower costs and what we can learn from Canada’s biosimilar programs.

Part 2: Wayne Winegarden, PhD, on What Canada Can Teach the United States About Biosimilars

A dysfunctional regulatory and market system is responsible for the high prices of drugs and the slim foothold that biosimilars have achieved so far in the marketplace, according to a position 

 from the American College of Physicians (ACP).

The group describes numerous structural impediments that hinder market entry for lower-cost drugs and allow pharmaceutical companies to leverage larger and larger revenues from their original brand products without a commensurate increase in health care consumer value.

ACP suggests multiple policy changes that would remove or loosen the blocks and wedges and allow competitors to step in with biosimilars and generic products that would lower health care costs without stifling innovation.

“New policies should be implemented to prevent market manipulation, help lower-cost alternatives make it to the market faster, and ensure a robust and competitive market for generic and biosimilar drugs,” ACP said.

The United States produces 57% more new drugs than the United Kingdom, Japan, Germany, and France combined, but many new drugs are simply repurposed old drugs with new indications, and meanwhile, there are thousands of rare diseases for which treatments exist for only a tiny fraction, ACP said.

Many Americans have benefited from the development of “orphan drugs” for niche health conditions (≤ 200,000 patients), but these are generally very costly, and ACP states that an orphan drug might be only a rare disease indication for a commonly used drug. Because of its orphan status, that same drug would be granted an additional 7 years of product exclusivity, preventing lower-cost competition from exerting downward pressure on pricing.

“This puts a strain on patients and families affected by rare diseases, who are often already exposed to high direct and indirect costs of medical care,” ACP noted.

ACP described the American marketplace as “unregulated” when it comes to pricing freedom enjoyed by pharmaceutical producers. “The list prices for the originator rheumatoid arthritis drugs Enbrel (etanercept, Amgen), Humira (adalimumab, AbbVie), and Xeljanz (tofacitinib, Pfizer) have increased by more than 100% since 2014,” the group said.

Biosimilars have been approved for etanercept and adalimumab but because of patent protections will effectively be kept off the market until 2029 and 2023, respectively. “Preventing lower-cost biosimilar or generic drugs from entering the market adds billions of dollars in costs to federal health care programs and affects the affordability and accessibility of drugs for patients who rely on them on a day-to-day basis,” ACP said.

Patent protections for biologics extend to 12 years in the United States, which the group said is excessive. Product exclusivity is often considered essential to reward companies for innovating and compensate them for the costs of developing a new drug; however, ACP argues that even after loss of exclusivity and biosimilar products enter the marketplace, a pharmaceutical company is able to continue making sizeable profits from a drug.

According to the Pacific Research Institute, the first biosimilar for filgrastim—and, in fact, the first-ever biosimilar in the United States—was launched in 2015, and since that time, filgrastim biosimilars have achieved only a 50.4% share of the marketplace for filgrastim, which supports the ACP’s contention that originator brands can continue making money after their patents have expired.

Manufacturers and industry insiders have contended that the 12-year window for product exclusivity is largely an illusion because many factors may 

 that time, such as a delayed approvals process. 

Insulin product approvals have recently come under regulation via the Biologics Price Competition and Innovation Act, which affords them biosimilar status if they are not originator drugs. It is hoped that this will lead to greater price competition, and ACP noted that the absence of competition for insulin products has allowed manufacturers to control the marketplace and steadily increase prices. “The annual cost per patient for treatment of type 1 diabetes doubled between 2012 and 2016, from $2864 to $5705,” the group said.

“Shadow pricing” is a type of marketplace abuse that ACP described as particularly damaging to health care consumers. With shadow pricing, a small number of dominant producers raise their prices almost in tandem. “Between 2009 and 2015, the prices of the insulin products Lantus (Sanofi-Aventis) and Levemir (Novo Nordisk) increased at or around the same time 13 times. Similarly, the prices of Humalog (Eli Lilly and Company) and NovoLog (Novo Nordisk) increased in conjunction 17 times over 10 years,” ACP said. 

The ACP called for legislative reform to the Orphan Drug Act to change incentives for development of these drugs. It supported reducing data and market exclusivity for biologic drugs from 12 years to 7 years and bringing a halt to “excessive patenting” on brand name and biologic drugs.

The group also called for elimination of direct-to-consumer (DTC) drug advertisements. “There is a lack of consensus in the economics literature about whether DTC advertising improves market performance or undercuts competition,” the ACP said.

Daniel H, Serchen J, Cooney TG. Policy recommendations to promote prescription drug competition: a position paper from the American College of Physicians. 

The American College of Physicians (ACP) said many reforms are needed to install appropriate checks and balances in the biologic drugs marketplace. 

ACP Calls for Biologics Marketplace Reforms

of individuals with rheumatic diseases found that 28.91% of patients weren’t sure whether they have been prescribed a biosimilar, indicating that there is a lack of knowledge about biosimilars and how they compare with reference products.

Additionally, about 35% of surveyed patients reported that they were prescribed a biosimilar medication.

The survey was conducted in June by Rheumatic Disease Awareness Month 2020 and the American College of Rheumatology (ACR) and its Simple Tasks public awareness campaign.

The survey builds on the ACR’s 2019 National Patient Survey and provides new insights into how issues regarding rheumatic diseases have changed over time, especially during the coronavirus disease 2019 (COVID-19) pandemic.

Prior authorization was required for nearly half (47.94%) of patients, according to the June survey. Previous reports have shown that prior authorization requirements can 

 to lower-cost medications such as biosimilars and prolong a patient’s waiting period before receiving treatment.

Step therapy requirements affected 46.17% of surveyed patients. Step therapy, also known as 

 patients to begin treatment using therapies preferred by their insurance company—usually less expensive drugs, such as biosimilars and generics—prior to trying a more expensive reference product.

In general, annual median out-of-pocket expenses more than doubled over the past year, rising from $475 in 2019 to $1000 in 2020. Furthermore, in the June survey, 26.68% of patients reported spending more than $2000 in out-of-pocket costs.

Reported wait times to be seen by a rheumatologist have increased, with 17.13% of patients waiting between 61 to 90 days to get a first appointment with a rheumatologist following a referral, compared with 13.39% in 2019.

“These results could be attributed to factors such as the COVID-19 pandemic, an increase in the number of individuals without health insurance, and the growing nationwide shortage of rheumatology health professionals,” authors of the report wrote.

About 66% of patients reported that they had taken advantage of telehealth within the past year, with 52% of patients citing the pandemic preventing them from being seen in the office as the main reason.

there was a 52% decline in the percentage of respondents who said they were currently being treated by a rheumatology provider. In 2020, 33.53% of patients surveyed said they were currently receiving treatment, compared with 57.41% of respondents in 2019 who said they were being treated by a rheumatology provider. Of those who reported that they were not being treated by a rheumatology provider, 38.23% said they used to be.

Many patients with rheumatic diseases are unsure whether their prescriptions are biosimilars, suggesting more efforts in patient education are needed.

ACR Survey Reveals Patient Knowledge Gaps on Biosimilars

for Merck’s Brenzys etanercept biosimilar by Health Canada. Originally approved in 2016 for the treatment of moderate-to-severe rheumatoid arthritis in adults and ankylosing spondylitis, Brenzys now has several additional approved indications: plaque psoriasis (PsO), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA).

Brenzys references Enbrel, which is already indicated by Health Canada for all the above-named indications. The drug is administered by subcutaneous injection.

In its statement about the expanded uses, Merck noted that roughly 1 million residents of Canada live with psoriasis and, of those, at least 10% will go on to develop PsA.

Etanercept is a tumor necrosis factor (TNF) blocker that reduces the amount of TNF-alpha made by the body’s immune system. Too much TNF-alpha is a characteristic of PsO, PsA, and JIA. This overproduction leads to painful, swollen joints and the development of thick, red, scaly patches known as psoriatic skin lesions, which can appear on any part of the body. Etanercept helps to ease these conditions.

JIA is the most common type of arthritis in children under the age of 16 and in Canada, roughly 10,000 youths have this condition.

“Merck is committed to providing Canadians with more therapeutic choices for patients and their treaters,” Anna Van Acker, president of Merck Canada, said in the statement.

Under the category of PsO, Canada Health has approved Brenzys for the treatment of adults with chronic moderate-to-severe PsO who are candidates for systemic therapy or phototherapy and also pediatric patients 4 to 17 years of age with chronic severe PsO who are candidates for systemic therapy or phototherapy.

In patients aged 4 to 17 years with an inadequate response to disease-modifying antirheumatic drugs, Brenzys is approved for the treatment of moderate-to-severe polyarticular JIA.

Various Canadian provinces are moving aggressively toward implementation of biosimilars in an attempt to save money and improve access to health care. British Columbia is furthest ahead with these initiatives and recently reported total savings of $96.6 million, which it plowed back into health system investments that made other forms of care more available for patients.

In the most recent phase of this transition, British Columbia established 

to biosimilar rituximab for patients in its PharmaCare prescription coverage plan. Other Canadian provinces are following suit with similar switching programs, but the overall usage picture for biosimilars in Canada shows that the market for these drugs remains small. 

Biosimilars have 8% of the Canadian market relative to originator products. In the United States, biosimilars command just 2.3% of the biologics marketplace, according to a recent Pfizer presentation.

A broader range of indications in rheumatology combined with a Canadian push for biosimilar acceptance bodes well for Merck's Brenzys product. 

Merck's Etanercept Gains More Indications for Use in Canada

 resulting in a $70 million damage award for Amgen formed the crux of a recent panel discussion aimed at broadening understanding of when biosimilar developers may overstep and incur infringement liability.

Intellectual property law attorneys from Goodwin Procter of Boston discussed “safe harbor” laws that allow biosimilar developers some protection against patent infringement during the product development phase. The law tolerates, or allows, patent infringement if it is “reasonably related” to the development of evidence or information needed for a biologics license application to the FDA.

, the courts upheld the $70 million jury verdict that Hospira had infringed 2 patents in the development of a biosimilar for Amgen’s epoetin alfa (Epogen) product, a recombinant human erythropoietin for the treatment of anemia. The courts found that the safe harbor provision protected just 7 of 21 batches of drug substance created for the testing and development of Hospira’s biosimilar version of the Amgen product.

The law leaves open to interpretation just what the intention was in the use of patented material, and whether this use was strictly intended for the support of an application for biosimilar approval, the panelists said. The courts have acknowledged that transgressing patents may be necessary during the development stages even though, ultimately, the knowledge gathered and the uses to which the patented material was put were not directly related to the FDA approval application.

“A potential infringer does not lose protection for a particular activity just because many aspects of drug development have dual or multiple purposes,” said Josh Weinger, an associate in Goodwin’s Litigation Department. 

The safe harbor provision “extends beyond activities that are purely necessary to seek approval for a drug,” Weinger said. For example, safe harbor allows biosimilar developers “to experiment without perfect clarity with respect to what the FDA is going to require to demonstrate [biosimilarity], so even if the biosimilar developer is not entirely sure what they’re going to need to do to meet FDA requirements, they have a good deal of flexibility.”

“I think the main distinction ends up being whether the [batch] testing is sort of the foundational testing as part of the application, or if it’s more of a routine testing of that particular batch,” Weinger. He defined routine testing as that which occurs after the FDA application package is complete, which “is a situation where there will be more risk of the safe harbor not applying.”

, the jury distinguished between the batches specifically for regulatory approval and those that were not necessary for that purpose. A lot of power rests with the jury in making that distinction, and on appeal the jury verdict was affirmed by the district court (Delaware) and the Court of Appeals for the Federal Circuit. “It’s not clear that if the jury had come up the other way, that decision wouldn’t also have been affirmed, so I think the jury has a fair amount of discretion to come out either way,” Weinger said.

Panel moderator Elaine Blais, head of the Litigation Department in Goodwin’s Boston office, said that based on that outcome, parties to such a case should consider whether there are ways to steer the case to a jury trial or prevent that from happening, based on relative advantages. “There are always considerations whether you want a bench trial or a jury trial,” she said.

), which governs the unauthorized import of a product produced outside of the United States using a process patented inside the United States, which is considered infringement. This section also provides protection against infringement for processes that involve use of patents but result in a material alteration such that the patented product becomes a “trivial or nonessential component of” the final product.

“In the chemical and biotechnology context, the general rule is that a significant change in structure and properties would be a material change. Of course, that’s still somewhat ambiguous,” said panelist Kevin DeJong, an associate with the Goodwin litigation group. “The inquiry is definitely a context dependent, factual determination. “

The courts may also consider whether it would be impossible to make the product without the patented process in question. “For example, a product that can only be made by the patented process may not be considered to be materially changed,” he said.

This section of the law was created in 1988, and prior to that time patent owners had “no real remedy against infringers who would import a product into the United States when it was made outside the United States using the patent method,” DeJong said. The implication for biosimilar developers is that they should be diligent about understanding any patents that might be involved in, for example, cell culture processes and purification.

Courts have allowed biosimilar developers "safe harbor" against infringement suits, but there are limits, attorneys from Goodwin Proctor explain.

Goodwin Attorneys Discuss Hospira-Amgen Infringement Case

 in the House of Representatives would allow for biosimilar insulins to automatically be granted interchangeability designations. Interchangeable status enables prescriptions to be filled with lower-cost biosimilars, without a prescribing physician’s authorization.

Currently, the FDA has acknowledged that clinical and analytical evidence for the safety and efficacy of some insulin products may be strong enough to eliminate the need for additional studies to demonstrate interchangeability; however, its current policy is to not grant automatic interchangeable status for insulins that are approved as biosimilars.

 from being regulated under the Food Drug and Cosmetics Act to being regulated under the Biologics Price Competition and Innovation Act (BPCIA). HR 8190 will amend the Public Health Service Act portion of the BPCIA by deeming “any insulin that is determined…to be biosimilar to the reference product” would be interchangeable with the reference product.

The bill’s sponsor, Representative Glenn Grothman, R-Wisconsin, told The Center for Biosimilars

 in an interview that policies such as his are necessary to help lower costs for patients, especially those within the juvenile diabetes community, with whom Grothman regularly works.

“You've got a situation in which parents can be stuck paying hundreds of dollars, maybe $1000 a month for something their child needs to survive. And it's just really unacceptable,

. "It crimps the whole family and puts them in a financially difficult situation. If we could get more access to biosimilars, we could make these folks lives much easier.

Removing barriers to interchangeability of biosimilar insulins would make insulin much more affordable for patients who need it, he said.

Grothman said that HR 8190, also called the Biosimilar Insulin Access Act of 2020, would apply to biosimilar insulins and clinically equivalent products that are not classified as biosimilars, such as Biocon and Mylan’s 

, which launched on the US market in August 2020. It also would apply to products that receive approval before and after the bill’s potential enactment.

Currently, there are no insulin products that have received interchangeability status from the FDA. However, Biocon and Mylan, are 

 to establish Semglee as an interchangeable biosimilar insulin. Semglee is not technically a biosimilar because it was approved under the former regulatory pathway under the Food Drug and Cosmetics Act, not under the BPCIA, which now governs insulin approvals.

The main limitation of the bill, Grothman said, concerns the interchangeability of biosimilars overall. Grothman said the bill is restricted to insulins because it’s likely going to be “easier to determine if a switch causes adverse reactions in patients on insulin than with other biosimilars.

“I would argue that it's a little bit safer, because people who need insulin are always getting check-ups. So, if there's something wrong, we find out right away,” he said.

Grothman added that, politically, addressing the interchangeability of biosimilar insulins is a good first step in the fight for similar changes to the way biosimilars are regulated and approved.

“If it works out, it's going to be hard for people for people to object….I think throughout life, once you demonstrate that one product works, it's easier to move on to a similar product and I hope that's what's going to happen here,” Grothman said.

After being introduced to the House, HR 8190 was referred to the House Committee on Energy and Commerce. Grothman’s next steps are to educate his fellow congressmen on the bill’s details in a search for co-sponsors and to build support for the measure.

“The more people hear about the potentially huge cost saving with biosimilars, the more Congress is going to be amenable to moving this on through," Grothman said. "And that's why we're going to ask for anybody to call your congressman, if you're familiar with the issue, and say, ‘Hey, what's going on? Why can't this bill move forward?’”

Going forward, Grothman anticipates some pushback from those with something to lose, such as those who view biosimilars as a threat to something they are already benefitting from.

“That's one of the reasons why it's all always difficult to get things through Congress,” he said.

Since March, 3 other biosimilar bills were introduced in Congress: a Senate bill aimed at 

 out-of-pocket expenses for biosimilars within Medicare Part B and companion bills in the House and the Senate regarding 

. So far, none of them have moved further than committee referral.

Representative Glenn Grothman, R-Wisconsin, says interchangeability for insulins makes sense based on the savings potential and safety record of these agents.