The Department of Justice (DOJ) recently filed a brief with the Supreme Court arguing that the Affordable Care Act (ACA) should be found unconstitutional. Although the brief was focused primarily on 3 insurance coverage provisions of the ACA, the DOJ also argued that even the “ACA’s comparatively ‘minor,’ ancillary provisions” are inextricably intertwined and should fall with the unconstitutional provisions. One of the many “minor, ancillary provisions” that would fall under the government’s argument would be the Biosimilar Price Competition and Innovation Act (BPCIA). The BPCIA established a framework for exclusivity for novel biological products and FDA approval of lower-cost “biosimilar” versions of such drugs. It also provided a system for litigation of patent disputes involving those products. It is projected that by 2026 the BPCIA will have saved over $50 billion for patients, health care payers, and providers.

The BPCIA has been far from a perfect system, and arguably it has not achieved its goal of meaningfully reducing the cost of life-saving biological products in the United States. In fact, the United States lags significantly behind the European Union and India in biosimilar approvals and cost savings. And because it is less than ideal from both a patient and business standpoint to toss the BPCIA framework out without a viable system to replace it, now is the time to consider what works well with the BPCIA and what improvements should be made. After all, instead of just blaming the cow, Chicago dealt with the great fire by building one of the world’s greatest skylines.

So, here is what we like about the BPCIA and the 6 things that we would change if we go back to the biosimilars drawing board.

What to Keep: The Approval Standard and the Opportunity for Interchangeability

There are 3 positive aspects of the BPCIA that ultimately should be retained.

: Initially the subject of frustration and derision, the standard for approval of biosimilars is the appropriate standard from a scientific and safety perspective and should be retained. The BPCIA requires that for approval a biosimilar must be demonstrably “highly similar to the reference product, notwithstanding minor differences in clinically inactive components.” There should also be “no clinically meaningful differences in terms of safety, purity, and potency.”

 The statute further provides that this standard can be met through analytical studies, animal studies, and clinical studies, with a focus on the assessment of immunogenicity.

 Companies were initially frustrated because neither the statute nor FDA regulations described the quantum of evidence needed to demonstrate that the “highly similar” standard has been met. But the FDA is becoming more familiar with the types of information it should be seeing from applicants, and therefore, approvals (until very recently) were increasing. In addition, the FDA has established a system of meetings for applicants to discuss their plans for submitting their applications and ways to resolve issues in those applications. Although the regulatory process can still be improved through experience, the statutory standard for approval is the correct one to ensure the safety and efficacy of biosimilars.

 of interchangeability is also a key aspect of the statute that should be retained, although the mechanism needs tweaking, as discussed below. Interchangeability allows a pharmacist to fill a prescription for a higher-cost branded drug with the lower-cost biosimilar version of the same product. This mechanism exists for traditional, small molecule drugs based solely on proof that the active ingredient is the same and that it will result in a similar amount of drug being available in the body as the branded version. No additional clinical trials for efficacy or safety are required. Automatic substitution has resulted in substantial cost savings to consumers and increased market penetration for small molecule products. But biosimilar manufacturers seeking interchangeability in the US market must run complex clinical trials, proving that the drugs will maintain efficacy if patients are switched between the brand and biosimilar products. The complex scientific proof that is required and the high cost of the trials have resulted in no awards of interchangeability in the United States, and the lack of a meaningful opportunity for interchangeability is the primary reason that companies are hesitant to pursue biosimilars.

Because it is unclear whether there will be an interchangeable biosimilar in the near future, the current approach to interchangeability has failed. However, interchangeability is an important statutory incentive for biosimilar applicants, and without it biosimilar applicants must compete with an existing biological product that is sold by a company that often has superior marketing power. The difficulty in attaining interchangeability should not be a reason to abandon it with a new statutory regime; it is incumbent upon the FDA to devise regulations to make it scientifically attainable. We provide a proposal below that provides a further incentive for applicants to seek biosimilar approval.

Notice to sponsor of biosimilar application

: Finally, although the information exchange or “patent dance” provisions of the statute should be eliminated, any new statutory scheme should retain the requirement that the applicant notify the reference sponsor that a biosimilar application has been filed and is under review. Much like in Hatch-Waxman Act cases, such notification would be the trigger for a patent infringement lawsuit and additional exclusivity for the reference product. However, as we discuss further below, significant improvements to this notice requirement are needed.

If the ACA is found unconstitutional in its entirety, we propose that Congress make the following 6 changes to the BPCIA when it is constructing a new pathway for biosimilar approvals and litigation: (1) mandatory biosimilar dispensing for treatment-naïve patients; (2) expansion of the Purple Book; (3) first filer exclusivity; (4) limited period of exclusivity with a potential compulsory license; (5) elimination of the patent dance; and (6) streamlining of the resulting patent litigation.

Default use for treatment-naïve patients

: One of the primary reasons that biosimilars have not taken off in this country is that potential applicants are intimidated by the high costs and risks of the regulatory and litigation processes. Without a meaningful opportunity for interchangeability, the applicant will be forced to compete with the reference sponsor, who will likely be better equipped to market and detail their own product. However, if the statute creates a market for an applicant’s biosimilar product, then there is greater incentive for more companies to undertake the risks associated with filing a biosimilar application. To that end, Congress could mandate that all treatment naïve patients be treated with an approved biosimilar product, if available, unless the treating physician or patient opts out. Although the safety of switching from a reference product to a biosimilar has been debated, it is generally accepted that treatment-naïve patients can be safely started on a biosimilar. And because most biological products treat chronic conditions, this requirement will create a sustained market for the biosimilar applicant and incentivize competition. 

 that setting generic pharmaceuticals as the default option has been shown to increase generic prescribing rates. The same should be expected for biosimilars. This approach would provide patients access to lower-cost treatments, which has been shown to increase medication adherence and thus reduce preventable morbidity and mortality. We would suggest price controls on the applicant in order to receive this benefit; for example, requiring the biosimilar to be priced at a 25% discount from the average sales price of the reference product over the last 5 years. The applicant should also have to maintain that price (absent competition) for at least 2 years.

: In the context of small molecules and Hatch-Waxman, the FDA’s Orange Book has been a useful tool—sponsors have been able to give notice to the public as to what patents purportedly protect their product, and applicants have a better understanding of the patent landscape that could be facing them. On the other hand, the Purple Book for biological products contains very little useful information. In fact, there has been proposed legislation to expand the Purple Book. Those calls should be heeded. As with the Orange Book, sponsors should be required to list in the Purple Book patents covering their approved biological product, and applicants should be required to submit a certification to FDA as to each listed patent that the applicant will not launch its biosimilar product until after the patent expires or that the patent is believed to be invalid and/or will not be infringed by applicant’s biosimilar product if marketed. Unlike the Orange Book, however, the Purple Book should include relevant process patents, because the process for making a biologic product is more often the subject of patent protection. The Purple Book should not include any use codes, and there should be penalties for improper listing of patents in the Purple Book.

: There is currently no exclusivity provided for the first biosimilar applicant to file an application. As a further incentive to encourage filing of biosimilar applications, there should be a 6-month exclusivity period for the first applicant to file a biosimilar application, which would be forfeited if that first filer does not obtain approval within 3.5 years of filing and launch its product within 2 years of approval of its application. This approach would be similar to the first-filer exclusivity period under Hatch-Waxman.

Limited exclusivity and compulsory licensing

: Instead of the current 12 years of exclusivity, Congress should separate the exclusivity period and provide a compulsory licensing period if litigation runs too long. Our proposal would grant a reference drug sponsor a total of 8 years of exclusivity prior to compulsory licensing while allowing biosimilar applicants to challenge patents 5 years into the exclusivity period. Under this approach, the sponsor should be provided a 5-year period of exclusivity during which no biosimilar application may be filed. After that 5-year period, the applicant can file an application referencing that biological product. Like with Hatch-Waxman, the applicant would be required to file with FDA a certification of patent invalidity and/or non-infringement as to every patent listed in the Purple Book, and must inform the sponsor of its application and certifications once FDA begins formal review. If the sponsor files suit in 60 days from receipt of notification from the applicant, then the biosimilar application shall not be approved for 3 years (earlier if the applicant is successful in the litigation). If this sounds like Hatch-Waxman litigation, well it’s very similar. The twist is that if the litigation is still pending after 3 years and the biosimilar application is already approved, the reference sponsor will provide a nonexclusive license to the applicant that will allow the applicant to launch its product and set a standard for damages in the event the launch was improper. Compulsory licensing schemes for pharmaceuticals have been proposed in other countries, such as the United Kingdom, and the international Agreement on Trade-Related Aspects of Intellectual Property Rights already allows for compulsory licensing in some situations.

: One of the most bemoaned aspects of the BPCIA is the so-called patent dance, and with good reason. It is confusing, causes unnecessary delay, and frequently involves gamesmanship. We propose eliminating it in its entirety. Under a new statute, applicants would be required to inform the sponsor of the certifications it provided to the FDA and provide information regarding its application so that the sponsor can determine which patents to assert. Applicants would not be required to provide detailed reasons for their certifications: Lawsuits are inevitable regardless of what is included in the detailed statement, and court-required contentions in patent cases provide advanced notice of the applicant’s patent invalidity arguments well before trial. Applicants would be permitted to restrict review of information to outside counsel eyes only, which would include independent expert review. As stated above, if the sponsor files suit within 60 days of receipt of this information, then they are entitled to another 3 years of exclusivity.

 Finally, the resulting patent litigation can be improved by a statutory requirement limiting the number of patent claims asserted in the litigation. The statute could require the number of asserted claims to be limited by the end of fact discovery, and it could limit either the total number of asserted claims or limit the number of claims per patent family or based on patent subject matter. In addition, patentees could ask the court to increase the number of asserted claims upon a showing of good cause.

In the 10 years since the BPCIA has passed, we have had the opportunity to learn many of the strengths and weaknesses of the act as passed within the Affordable Care Act. If either the Supreme Court or Congress ultimately determines that portions of the ACA are to be repealed, the fundamental premise of the BPCIA should be preserved or reissued in order to improve patient access to lower-cost medical treatments. At the same time, the important lessons learned should also be implemented in the form of the changes we have proposed here. As with the rebuilding of Chicago after the fire, a better version of the BPCIA is possible with careful planning and vision.

1. Regulation of Biological Products. §262(i)(2), 42 USC (2017).

2. Regulation of Biological Products. §262(i)(2)(A)(i)(I)(aa)-(cc), 42 USC (2017).

IP Attorneys Propose a New Biosimilar Pathway in Case of ACA Repeal

Joel M. Wallace is an intellectual property attorney 

Joel M. Wallace

Sourced-Center for Biosimilars Staff

Madelaine Feldman, MD, is a rheumatologist in private practice with The Rheumatology Group in New Orleans, Louisiana. She is president of the Coalition of State Rheumatology Organizations, which is a founding member of the Alliance for Transparent and Affordable Prescriptions. She is also chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology’s insurance subcommittee.

Madelaine Feldman, MD

Christine Simmon is the executive director of the Biosimilars Council and senior vice president of policy and strategic alliances at the Association for Accessible Medicines (AAM). Christine leads policy development and issues management for AAM and has led the Biosimilars Council since its founding in 2015.

Christine Simmon

As the biosimilar market continues to expand, many health systems and insurance companies will start making the decision on what product—the innovator or the biosimilar&mdash;will be on their formulary. Health systems will have a difficult time making this decision, which will be driven by their medical staff’s acceptance of biosimilars, the patient mix, and the predominant insurance provider. Making the decision to use or not to use a biosimilar is much more complex than converting to a generic product or switching agents within a therapeutic class.  

The ultimate formulary decision requires the evaluation of multiple factors as listed below: 

 If physicians do not accept the biosimilar’s qualifications as a product of equal safety and efficacy as the originator biologic, formulary management will be very difficult, and there is the potential for errors with having to carry multiple products.  

Not all pharmaceutical wholesalers will supply the product. Most pharmacy departments purchase products from the wholesaler at a cost minus. If the biosimilar does not come through the wholesaler, the pharmacy is charged a higher price.  

—eligible, providing a competitive 340B price is critical to the formulary decision.   

 For hospitalized patients (inpatients), drugs are reimbursed as part of a diagnosis-related group (commonly known as DRG); so the best-priced product is the preferred product. However, on the outpatient side, the price of the product is as important as the reimbursement. It is important to monitor the reimbursement of outpatient biosimilars to evaluate the overall reimbursement, as the average sales price (ASP) erodes over time. Biosimilars are to be reimbursed at 100% of the ASP for the biosimilar, plus 6% of the ASP for the originator biologic.

 Often, the products are bundled with other products within the company’s portfolio. The overall impact to any existing contracts or rebates need to be calculated.  

 This is an important consideration when determining product storage and dispensing. Changing from a vial to a syringe may require purchasing larger refrigerators for storage. 

 The resources necessary to build the medication record and convert patients will need to be calculated. In addition, new insurance authorizations will be required since the products have different J-codes.

Given that the United States is considerably new in the biosimilar market, the exact degree to which prices will drop remains unknown. The ability to control biologic drug expenditures is challenging because of the complexities of the pharmaceutical supply chain and reimbursement. Overall, one of the most difficult things related to biosimilars will be the ability to accurately predict their value to your health system. It is critical that pharmacists and other stakeholders in the formulary decision process understand the complexity of calculating the overall impact of biosimilars.   

Formulary Management an Important Consideration for Biosimilar Stakeholders

Molly Billstein Leber, PharmD, BCPS, FASHP

Amanda DeMarzo, PharmD, MBA, PACS, is associate director of Patient Access with the National Board of Prior Authorization Specialists, an affiliate of the Accreditation Council for Medical Affairs, based in Oradell, New Jersey. Amanda focuses on how to improve the current health care system as a whole through improved training, widespread certification, and advanced technology for better patient outcomes. She developed a passion for patient-centered care and shared decision-making during patient-facing roles over the last 8 years.

Amanda DeMarzo

In its newly released earnings report for Q4 and fiscal year 2021, Coherus announced Udenyca—one of 4 pegfilgrastim biosimilars on the US market—delivered net sales of $73 million and $327 million, respectively.

But totals were down from those reported in 2020, with Udenyca earning a net $110.4 million in Q4 of 2020 and $475.8 million throughout the year. Decreases were mainly due to a reduction in the number of units sold and a decline in net realized price resulting from increased competition and COVID-19 impacts, the company said in a 

Udenyca is a colony stimulating factor that promotes white blood cell growth and is used to treat neutropenia resulting from cancer medications.

Coherus reported net losses for 2021 Q4 of $45.7 million, or $0.60 per share on a diluted basis compared with totals recorded in the same period in 2020; net losses were also recorded for 2021 as a whole ($287.1 million, or $3.81 per share on a diluted basis, compared with net income of $132.2 million, or $1.62 per share, on a diluted basis for 2020).

From 2020 to 2021, research and development (R&D) costs increased from $142.8 million to $363.1 million, due in large part to an upfront license fee paid to Junshi Biosciences. Costs incurred from the development of Yusimry, toripalimab and additional presentations of Udenyca also contributed to the $220.3 million rise.

Selling, general, and administrative (SG&A) costs increased year over year from $139.2 million in 2020 to $169.7 million in 2021.

In 2022, Coherus expects to launch 2 new products and initiate a clinical trial evaluating toripalimab in combination with JS006, company CEO Denny Lanfear said.

“Looking ahead to 2023, we project accelerating revenue growth with the planned launch of FDA-approved Yusimry into the $17 billion Humira market and the introduction of the Udenyca on-body injector, if approved, a new presentation that would enable us to address the remaining $1.2 billion Neulasta Onpro segment of the pegfilgrastim market where there is currently no biosimilar competition,” Lanfear added.

The company also projects combined R&D and SG&A expenses in 2022 will be in the range of $415 million to $450 million as a result of the anticipated new product launches and the additional presentation of Udenyca.

In its report, Coherus touted the FDA approval of 

 (adalimumab-aqvh), a Humira biosimilar in December 2021 and a biologics license application (BLA) for Cimerli (ranibizumab-ranq), a Lucentis biosimilar which has an assigned a target action date of August 2022.

An April 2022 target action date has been set for toripalimab’s BLA for the treatment of metastatic or recurrent nasopharyngeal carcinoma. It is currently under priority review by the FDA for this indication and is being studied for treatment of lung, breast, liver, skin, kidney, stomach, esophagus, and bladder cancers.

Coherus released its earnings report for the last quarter of 2021 and for the year as a whole. 

Coherus Banks on 2022 Approvals After Net Losses for Q4, 2021

Gianna Melillo

What are your thoughts on the recent launch of Renflexis in the United States?

I think that it will be very interesting to see what happens now that we have 3 versions of infliximab on the market. Will this drive the cost down? I think that it remains to be seen. I think, as you look at what has happened since the first biosimilar for infliximab has hit the market, you have seen insurance companies—United, for example, actually signed a contract with Remicade to stay with the bio-originator. I think you are going to see some of this, but I think it will be interesting to see the uptake and how this happens, and I think we will start to see the outcomes of this moving forward.

Marcus H. Snow, MD, Assistant Professor Rheumatology, University of Nebraska, discusses the recent launch of a new biosimilar infliximab, Renflexis, in the United States. 

Dr Marcus H. Snow: The US Launch of Renflexis

Marcus H. Snow, MD

Sandoz said Tuesday the the FDA approved its citrate-free, high-concentration formulation (HCF) of its adalimumab biosimilar, Hyrimoz.

The adalimumab-adaz injection (100 mg/mL) is approved to treat 7 indications covered by the reference product, Humira, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn disease, ulcerative colitis, and plaque psoriasis.

“As one of the first adalimumab high-concentration formulation biosimilars approved in the US, Hyrimoz HCF has the potential to expand access for millions of people who face the realities of living with a serious inflammatory disease and to enhance the patient experience,” Keren Haruvi, president, Sandoz Inc., head of North America, 

Sandoz set a launch date of July 1 for both versions of Hyrimoz.

The FDA approval was based on a phase 1 pharmacokinetics (PK) bridging study comparing the FDA-approved adalimumab 50 mg/mL to the citrate-free, HCF 100 mg/mL. This study met all of the primary objectives, demonstrating comparable PK and showing similar safety and immunogenicity of the low-concentration adalimumab and the HCF adalimumab.

The original, low-concentration version of Hyrimoz was approved by the FDA in 2018. Another HCF version, Hadlima, from Organon and Samsung Bioepis, was approved in August 2022. Biologics license applications for Alvotech and Celltrion Healthcare's high-concentration adalimumab biosimilars are currently under review with the FDA.

In 2023, up to 10 adalimumab biosimilars will enter the market. The first, Amgen’s Amjevita, launched at the 

; as with Hyrimoz, the others are scheduled to launch starting in July 2023.

Both the high-concentration and low-concentration versions of adalimumab-adaz (Hyrimoz) injection will launch in July, along with a wave of other biosimilars to Humira (reference adalimumab).


FDA Approves Sandoz’ High-Concentration Version of Adalimumab Biosimilar, Hyrimoz

Allison Inserro

Celltrion presented data at the American College of Rheumatology (ACR) meeting on November 14, demonstrating that its product CT-P10 is as safe and effective as Rituxan for the treatment of rheumatoid arthritis (RA).

, investigators tested CT-P10 against both US- and EU-licensed versions of rituximab. The study evaluated pharmacokinetic and pharmacodynamics, as well as safety.

Three hundred seventy-two patients participated in the study. A total of 161 were given CT-P10 and the remainder were given the originator product.

The investigators concluded that the pharmacokinetics of CT-P10 were highly similar to those for the originator products (90% confidence intervals were within the equivalence range of 80% to 125%), and the safety profile was noninferior. Infusion-related reactions occurred in 6 (9.4%) of patients in the biosimilar group, 4 (6.2%) in the US-licensed version of rituximab, and 12 (20%) in the EU-licensed group, and all of these reactions were either grade 1 or 2. Discontinuations as a result of an adverse event occurred in 3.1%, 4.6%, and 1.7% of patients taking the biosimilar, US version, and EU version, respectively.

 at the American College of Rheumatology meeting,  a team of researchers sought to gather efficacy data on the biosimilar versus the two licensed versions of Rituxan, using the DAS28-CRP/ESR as a primary endpoint.They found in this phase 3, controlled study, that the biosimilar was therapeutically equivalent to the other treatment groups, with a change in DAS28-CRP of -2.14 for the biosimilar vs. -2.09 for the originator products. Additionally, the change in DAS28-ESR scores were -2.41 vs. -2.35, respectively. ACR 20, 50, and 70 scores were equivalent as well. No significant differences in adverse events were detected among the groups, and no serious complications were reported.

Biosimilar rituximab is being tested not only in patients with RA but in those with non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), and polyangiitis. If it is approved for treatment, Celltrion’s product would likely be the first CD20-inhibiting monoclonal antibody to reach the market in a biosimilar version.

Celltrion announced that on November 17, 

 for use in South Korea for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. It will be marketed under the name Truxima in that country.

Pharmacokinetics of CT-P10 were highly similar to originator products. 

Authors