Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Reykjavik, Iceland-based company Alvotech said it has begun 

 of a potential ustekinumab biosimilar (AVT04), referencing Stelara, in patients with moderate-to-severe plaque psoriasis.

Recruitment has begun for a confirmatory efficacy and safety study (N = 530) in Central and Eastern Europe and a separate, pharmacokinetic (PK) comparability study (N = 294) in New Zealand and Australia. The latter study also will evaluate for safety and tolerability.

Alvotech noted in a statement that the ustekinumab market represents a lucrative opportunity. The reference product had global sales of $7.7 billion in 2020. Janssen Biotech discovered ustekinumab and holds exclusive US rights to distribution. 

This marks the second Alvotech biosimilar candidate to enter clinical studies. The first was AVT02, an adalimumab candidate referencing a high-concentration form of Humira. Alvotech said a 

 is underway to support an interchangeable designation for AVT02 in the United States. The company said in June 2021 that it had reached the point where findings from the study could be reported to the FDA.

Biosimilars are approved as being equally safe and efficacious as originator drugs but the interchangeability designation would allow pharmacists to dispense the biosimilar in place of Humira without consulting the prescribing physician.

There are currently no interchangeable biosimilars approved in the United States, although at least 1 interchangeable insulin approval is anticipated in 2021. In Europe, where biosimilars are more widely used and accepted, pharmacists are sometimes directed to dispense biosimilars instead of originator products.

The FDA and the European Medicines Agency accepted regulatory approval applications for AVT02 in 2020. The company anticipates an FDA decision for AVT02 in September 2021 and an EMA decision in the fourth quarter of 2021.

For a recent interview with Alvotech's chief commercial officer about the prospects for AVT02, click 

Articles

AVT04 (ustekinumab) if approved would be targeted at an estimated $7.7 billion market for the reference product, Stelara. 

Alvotech's Ustekinumab Candidate Reaches Clinical Trial Milestone

Teva Pharmaceutical Industries and Bioeq said they would 

 to market the ranibizumab biosimilar candidate (FYB201) in Europe, Canada, Israel, and New Zealand. The proposed agent references Lucentis for macular degeneration.

FYB201 was originally developed by Formycon, which contracted with Bioeq for the submission of regulatory approval filings in the United States and European Union. “Bioeq will be responsible for the development, registration and supply of the biosimilar, while Teva will be responsible for commercializing the product,” the companies said in a statement. Formycon and Bioeq had hoped for a US launch in 2021.

published in May 2021, investigators concluded that FYB201 met the primary end point for efficacy and ocular and systemic safety in a trial of FYB201 vs reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration.

Primary end points were improvements in best-corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients were randomized equally to FYB201 or reference ranibizumab. BCVA improved by a mean of +5.1 and +5.6 ETDRS letters by week 8 for the ranibizumab candidate vs reference groups, respectively.

Biosimilars Overview for Oncologists, Patients

from the Alliance for Patient Access (APA) provides a clear and simple overview of biosimilars from the perspective of oncologists explaining why these agents make sense for patients and how they can improve access to health care.

The APA is a collective of health care providers from diverse practice specialties who advocate for clinical decision support, restraints on health care management policies by payers, and respect for individual health care needs.

Their new paper serves as a tutorial that could be shared with health care practitioners or patients to educate about biosimilars. “Biosimilars stand to benefit both physicians and patients. More treatments mean more opportunities to tailor care,” says a section on biosimilars for support of patient-centered care.

The paper also addresses the importance of physician confidence in biosimilars. “Ongoing real-world data also must be collected and relayed to physicians regularly,” the authors write.

The issues inherent in switching patients to biosimilars also are addressed. “It should not be discounted, particularly in the case of a lengthy battle with cancer, that patients also may have an emotional attachment to medication that’s working for them and not want to change,” the authors write.

Nonmedical switching often presents extra administrative burdens, they note. “Physicians and patients who want to challenge the insurer-directed switch must fill out forms, send letters, and make calls. Patients may need to sign a new consent form with the clinic for the change in treatment, which could undermine patient confidence and possibly create a perception of increased risk.”

The authors conclude, however, that biosimilars offer more treatment options, especially more individualized care, and potential for savings and improved allocation of health care resources.

Organon, a Merck biosimilars spinoff company, has 

the Biosimilars Forum, which is a consortium of biosimilars companies. Organon does not develop biosimilars. Rather, it contracts with established biosimilars companies that have completed biosimilar development and manages the sales of these products.

“While the policy environment for biosimilars is improving, we know there is a long way to go toward increased access to biosimilars,” Organon said about its decision to join the Biosimilars Forum. Payers are starting to give biosimilars preferred status. Cigna in June 2021 announced that it was placing 2 infliximab biosimilars, Avsola and Inflectra, on preferred formulary to incentivize use of these products. The pharmacy benefit manager also said it would initiate a 

 to patients who switched to biosimilars. That payment would come in the form of a health care debit card.

Renflexis, an infliximab biosimilar, Ontruzant (trastuzumab), Aybintio (bevacizumab), and Hadlima (adalimumab). The company also plans to market the etanercept biosimilar Brenzys.

The Biosimilars Forum includes Biogen, Boehringer Ingelheim, Coherus BioSciences, Pfizer, Samsung Bioepis, Sandoz, Teva, and Viatris. Merck also has been a member, although Merck announced at the time of the Organon spinoff that it was exiting from biosimilars activity.

Teva and Bioeq partner on ranibizumab, Organon joins the Biosimilars Forum, and the Alliance for Patient Access issues educational material for oncology biosimilars.

Biosimilars Roundup: New Ranibizumab Partnership, Organon Joins Biosimilars Forum, Oncology Educational Materials

Hoping to stimulate greater use of biosimilars, 28 patient advocacy groups have thrown their weight behind 

 that would increase Medicare reimbursement to health care institutions when they prescribe these agents for patients.

The draft legislation would impose a revision to a Medicare payment policy that has been changed before to stimulate biosimilar uptake.

Importantly, the policy only applies when a biosimilar’s price is lower than the price of the brand-name reference biologic. This guarantees savings to Medicare and reduces out-of-pocket costs for seniors.

Biosimilars advocates, including companies that produce and distribute biosimilars, contend that additional changes are needed to more successfully incentivize prescribers to choose biosimilars over reference products, which tend to cost more than biosimilars.

The 60 Plus Association, CancerCare, and Healthy Women are among the groups that have endorsed the Bolstering Innovative Options to Save Immediately on Medicines (BIOSIM) Act, which increase physician reimbursement for use of biosimilars.

“According to a recent analysis, women, seniors, and low-income individuals are expected to benefit most from increased access to biosimilars, as they are predominantly impacted by the conditions currently treated by higher-cost biologics for which biosimilar competition can reduce costs. However, despite average cost savings of 30%, biosimilar adoption continues to trail expectations,” the patient advocacy groups state in a letter supporting adoption of the BIOSIM Act.

The legislation has been spearheaded by the Biosimilars Forum and the Biosimilars Council, which represent producers and distributors of biosimilars and generic drugs.

Under current policy, Medicare reimburses based on the average sales price (ASP) of the biosimilar brand plus 6% of the reference product price. Prescribers who choose the reference product get 100% plus 6% of that product’s ASP.

The rationale is that if doctors got 6% of the lower-priced biosimilar, they would be incentivized to prescribe the higher-priced product every time, in order to get 6% of the higher value, and nobody would prescribe the lower-cost agent unless they were committed to saving money for Medicare.

 would increase the add-on percentage for biosimilar use to 8% of the reference product ASP, and reference product use would continue to garner just the 6% add-on. The 8% add-on would apply only to biosimilars that cost less than the reference products.

Once a biosimilar qualifies for the additional payment and a payment is made under this policy, the 8% rate would continue for 5 years for that particular biosimilar, assuming the biosimilar continues to qualify as a lower-cost product.

Originally, CMS calculated the ASP for all biosimilars in a category and arrived at a single base price. The add-on payment was still based on the higher reference product price. This was considered a “blended” payment formula.

However, one of the opposing arguments was that biosimilars were 

, because some were approved for more indications than others. This led to CMS issuing separate payment codes and reimbursement amounts for each biosimilar. Providers were then reimbursed based on 100% of the individual biosimilar’s ASP plus 6% of the reference product’s ASP.

Additionally, because it takes time to establish an ASP for newly marketed biosimilars, CMS initially reimburses biosimilar use at 106% of the wholesale acquisition price (WAC), which is what manufacturers charge drug wholesalers.

Under the BIOSIM Act, the WAC for a biosimilar also should not be more than the WAC of the reference product.

In their letter addressed to the sponsors of the legislation, Representatives Kurt Schrader (D-OR) and Adam Kinzinger (R-IL), the advocacy groups did not make the distinction that the 8% payment would apply to the cost of the higher-cost reference product, not the biosimilar. 

The BIOSIM Act would increase the add-on payment for use of a biosimilar, thereby incentivizing practitioners to use these products more often, according to proponents of the bill. 

Patient Advocacy Groups Offer Support for BIOSIM Act

A study of British patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) who were treated with the rituximab biosimilar Truxima vs the originator (Rituxan) demonstrated comparable efficacy and tolerability between therapies, according to a recent study.

Investigators analyzed data from 201 patients treated by 46 UK-registered hematologists and oncologists in this retrospective survey. They evaluated charts for adult patients who received the biosimilar or originator as first-line immunotherapy between January 1, 2018, and June 30, 2019.

The use of biosimilar rituximab yielded not only comparable outcomes but also average cost savings of $1385 per patient. “These findings should inform decision makers on the potential for cost reductions where the biosimilar [Truxima] is available as a treatment alternative,” the investigators said.

They noted high overall response rates (ORRs) and 6-month progression-free survival (96%-98%) across cohorts, as well as 1-year survival of 98% to 100% across cohorts.

ORRs for patients with CLL who received Truxima vs Rituxan were 97.9% and 93.9%, respectively. For patients with NHL, the respective ORRs were 94.0% and 95.9%.

Complete response (CR) rates for patients receiving the biosimilar vs originator were 64.6% and 67.3% for CLL and 68.0% and 73.5% for NHL, respectively. Partial response rates were 33.3% and 26.5% for CLL and 26.0% and 22.4% for NHL.

Treatment discontinuations due to progression, death, or initiation of a subsequent line of therapy were 12.8% and 12.2 % for patients with CLL receiving Truxima vs Rituxan and 12.2% and 10.4% for patients in the NHL cohorts, respectively.

The investigators said 54% to 66% of patients across cohorts did not experience grade ≥ 3 adverse events (AEs); the most common grade ≥ 3 AEs were neutropenia, fatigue, anemia, and infusion reactions.

They did note high health care resource utilization, including drug costs, diagnostic testing, office visits with oncologists, and hospital admissions.

McBride A, Daniel S, Driessen MT, et al. Real-world overall response rate and other outcomes related to originator and biosimilar rituximab in patients with chronic lymphocytic leukemia or non-Hodgkin’s lymphoma in the United Kingdom. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2021. Abstract e18696.

Investigators reported high overall response rates and savings of roughly $1400 per patient across cohorts. 

Truxima Produces Savings and Comparable Outcomes for UK Patients With CLL, NHL

Innovent Biologics, said the National Medical Products Administration of China has 

the use of its sintilimab programmed death–1 (PD-1) inhibitor (Tyvyt) in combination with the bevacizumab biosimilar Byvasda as first-line treatment for patients with advanced or unresectable hepatocellular carcinoma (HCC).

The company said this marks the first regulatory approval of a PD-1–inhibitor combination therapy for HCC in the front line. Via the binding of PD-1 proteins on immune cells to the PD ligand 1 (PD-L1) expressed on tumor cells, the immune reaction to cancer cells is “switched off.” PD-1 inhibitors help to prevent this switching off from happening, allowing immune cells to destroy tumor cells.

Liver cancer is the third leading cause of cancer death globally, and China accounts for over 50% of all new cases and deaths worldwide. The disease is a serious threat to the life and health of Chinese people and a heavy burden on society and families, with hepatocellular carcinoma accounting for 85% to 90% of all liver cancer.

Approval was based on findings from ORIENT-32, a randomized, open-label phase 3 trial of frontline Tyvyt in combination with Byvasda vs sorafenib, a kinase inhibitor that suppresses tumor growth, in patients with hepatitis B virus–related, unresectable HCC.

Patients in the combination arm had significantly longer progression-free survival vs patients in the sorafenib group (4.6 months vs 2.8 months, respectively; HR, 0.56; 95% CI, 0.46-0.70; 

 < .0001). The overall survival for the combination was not reached at data cutoff vs 10.4 months for the sorafenib group (HR, 0.57; 95% CI, 0.43-0.75; 

“In China, liver cancer is the second most common cause of cancer-related death and ranks fourth in terms of incidence with a 5-year survival rate of only 10%,” said Fan Jia, MD, of Zhongshan Hospital of Fudan University, Shanghai, China. He served as lead author on ORIENT-32.

Within the subset of liver cancer, HCC accounts for 85% to 90% of incidence, according to Yongjun Liu, president of Innovent.

He noted that patients with HCC do not respond well to chemotherapy or targeted therapy, creating a need for more powerful treatment options such as immunotherapy (PD-1 inhibitors). “ORIENT-32 has demonstrated that sintilimab plus bevacizumab can extend the overall survival and progression-free survival in this patient population and bring significant clinical benefits,” Jia said.

For further details on the positive findings reported from ORIENT-32, click 

Innovent Biologics is based in Suzhou, China, and has offices in San Francisco, California.

Innovent Biologics said based on success of ORIENT-32, China's National Medical Products Administration (NMPA) has approved sintilimab in combination with bevacizumab biosimilar (Byvasda) in front-line unresectable hepatocellular carcinoma. 

Innovent Gains NMPA Nod for Byvasda Combination in Unresectable HCC

that ranibizumab ophthalmology biosimilar candidate Byooviz (SB11) be approved for commercialization. Byooviz was developed by Samsung Bioepis and references the blockbuster medication Lucentis, a Novartis product that garnered $1.93 billion in 2020 sales.

Officials for Samsung Bioepis and Biogen, which would market the agent, said a final approval on marketing would make this the first biosimilar for Lucentis to be commercialized in the European Union.

The recommendation for marketing approval was from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), and the final decision on marketing authorization would be made by the European Commission.

Ranibizumab counters the development of blood vessels that contribute to retinal disorders such as neovascular (wet) age-related macular degeneration, diabetic macular oedema, macular oedema related to retinal vein occlusion, proliferative diabetic retinopathy, and choroidal neovascularization.

Officials said the positive CHMP opinion was based on successful phase 3 trial data demonstrating that outcomes for the biosimilar candidate were within prespecified margins for conformance with the originator product.

Mean changes from baseline in best corrected visual acuity and in central subfield thickness were measured. “The improvements in the primary efficacy outcomes remained stable and appeared comparable between treatment groups at all time points up to week 52,” officials said.

An application for Byooviz marketing authorization has been 

 by the FDA since November 2020. Samsung Bioepis and Biogen are also seeking to commercialize an aflibercept biosimilar candidate (SB15), which is currently in phase 3 trial evaluation.

Aflibercept also is a vascular endothelial growth factor inhibitor and is employed in the treatment of macular degeneration and metastatic colorectal cancer. There are currently no biosimilars for this product, which was developed by Regeneron Pharmaceuticals and is sold under the brand names Eylea and Zaltrap.

For more reading on Samsung Bioepis and its biosimilars initiative, click 

on anti–tumor necrosis factor inhibitors by Biogen investigators, click here. 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has favored marketing authorization for the ranibizumab biosimilar (Byooviz, SB11) based on phase 3 study findings. 

Samsung Bioepis, Biogen Get CHMP Backing for First Lucentis Biosimilar

It’s very likely that 2021 will be the year of the first interchangeable biosimilar, which pharmacists could substitute for an originator brand without asking the prescribing physician for approval. Expectations are that the FDA will approve at least 1 this year. 

As of April 2021, all US states had passed laws for how and when these can be used, according to Laura Sim, senior counsel for Development, Regulatory, Operations, and Contracting Law at Amgen.

All of these will allow pharmacists to dispense interchangeable biosimilars, provided the physicians have not stated that originator brands should be used, and some record of the interchangeable being prescribed must be made available to physicians. 

“A lot of the state laws also require that the patient be notified before the substitution takes place,” she said.

In some instances, these laws contain “sunset,” or automatic termination, clauses, which expire if they aren't reauthorized, which enables public officials to reconsider them, Sim said in a presentation at the American Cancer Institute’s 12th Annual Summit on Biosimilars and Innovator Biologics, held June 22-23, 2021. This is a sign of the great uncertainty that still surrounds interchangeable biosimilars and their pending debut, she noted.

“This area is still clearly developing on the regulatory side, and there are unknowns on the commercial implications of interchangeability; the next 3 to 5 years are going to be a critical, pivotal time for starting to really gauge how interchangeability will play out and the value it will have,” she said.

An FDA biosimilar approval is a declaration that the biosimilar is as safe and efficacious as the originator biologic it references, with no clinically meaningful differences, but to qualify as interchangeable biosimilars must go through additional regulatory hoops, such as switching studies to demonstrate that patients will have the same clinical outcomes whether they start on the reference drug and switch to the biosimilar or switch back to the reference drug after using the biosimilar.

An area that's pretty important that we haven't had definitive input yet from the FDA is what will be the durability of an interchangeability designation? Are there circumstances that could cause FDA to revisit whether an interchangeability designation should stand?

“It’s important to note that interchangeability does not confer any sort of clinical superiority. It does not mean any sort of higher quality vs biosimilars that have not received an interchangeability designation,” Sim said.

The FDA has indicated in recent guidance that a switching study generally will be expected to support an interchangeability designation and a sponsor should provide scientific justification for use of that product in a non–FDA-approved indication.

Having even that information won't erase the question marks hovering over the interchangeable designation, Sim said. What happens if an application device for a biosimilar is different from the type used for the originator? And what happens as different formulations of the biosimilar or originator are developed after an interchangeable designation has been assigned?

“What evidence is the FDA going to ask for to support those differences?” Sim asked. “Another area that’s pretty important that we haven’t had definitive input yet from the FDA is what will be the durability of an interchangeability designation? Are there circumstances that could cause the FDA to revisit whether an interchangeability designation should stand? For example, if the reference product and the interchangeable product drift apart over time, [biologics differ minutely batch to batch].”

“We also don't know if companies will be allowed to include in their label any data that they generated to support the interchangeability designation,” Sim said.

What remains to be seen is what are going to be the payer reimbursement inputs? Are payers going to look at interchangeability as a differentiator? How much weight is it going to hold in their deliberations?

Another question is how payers will react to the interchangeability designation. Will they give it more weight when they consider a drug for formulary placement? “I think we’re going to start to get some answers to these questions, or some early indications of how payers are thinking, in the next few years,” She said. 

On March 23, 2020, insulins and growth hormones began to be regulated under the Biologics Price Competition and Innovation Act, and this means that they, too, could be approved as biosimilars and interchangeables. But for insulins, the requirements for an interchangeable designation are far less stringent.

These agents are less complex than the typical monoclonal antibody biosimilar, and more is known about them via historical usage and development, so the FDA has indicated in guidance that it is comfortable not requiring clinical immunogenicity studies or switching studies to support interchangeable designations for these products, Sim noted.

“This is really a pretty big deviation from how the FDA has traditionally approached biosimilars and how they’ve approached other product areas,” she said. “It really pares back the expectations for clinical testing, but it’s in this narrow class of insulins, which is a fairly unique product class in a number of ways. And I do think it raises the question, at least, whether this may be a sign of some things to come potentially for other small, well-characterized [small molecule] biologics.”

Ultimately, the debate over the interchangeability designation will play out in the public forum, she said. “I think it’s fair to expect that we’ll have some litigation and some citizen petitions and the like over interchangeability designations. If we look at the generic space, a lot of these issues can be very contentious.”

A turning point for interchangeable biosimilars has arrived, as the first may be approved this year, but many questions about these agents have yet to be answered, according to Laura Sim, senior counsel for Amgen.

Amgen Executive Weighs the Challenges for Interchangeable Biosimilars

With specialty drug costs commanding an ever-larger share of the total pharmacy spend, the pharmacy benefit manager Cigna is unrolling a shared savings program that, among its signature features, offers patients a $500 health services/products gift card for switching to a biosimilar.

The Shared Savings Program serves as down payment on the future promise of biosimilars. At a time when many people are having to make difficult decisions related to how to afford their medications, this program will offer some direct financial relief and position customers and their employers to recognize greater long-term cost savings.

 2021 with more information presented to patients, but in announcing the program, Cigna Chief Clinical Officer Steve Miller stated that a chief goal is to reduce current spending on the infliximab originator product Remicade, which he said costs $30,000 yearly for an average regimen of infusions, “but may be much higher depending on site of administration.” 

“While life-saving and life-changing, this [medicine] presents a significant challenge for health plans and can be financially devastating for patients,” he said.

Also, Cigna will move 2 infliximab biosimilars, Avsola and Inflectra, up to preferred status on formulary to get patients and health care providers to use them.

Infliximab is used in the treatment of rheumatoid arthritis and other types of autoimmune diseases. Infliximab biosimilars have seen 

 compared with other biosimilars. Clinical investigators have speculated that physicians are more reluctant to switch patients to a biosimilar form of infliximab once hard-to-manage chronic autoimmune conditions are brought under control with the reference product.

After 3 years on the market, infliximab biosimilars had achieved just 20% of the total market for infliximab, according to a

 from Amgen. However, steep declines were noted in average sales price (ASP) for the reference product and the biosimilars available at that time, indicating that biosimilar competitive pressure had succeeded in lowering overall costs of infliximab.

By the second quarter of 2020, Remicade’s ASP had dropped 33%, and the 2 biosimilars on the market at that time, Inflectra and Renflexis, had seen ASP price drops of 43% and 40%, respectively. In July 2020, Amgen launched the infliximab biosimilar Avsola. The respective ASPs at the time for Remicade, Inflectra, Renflexis, and Avsola were $483, $471, $486, and $500. 

Manufacturer deals and rebates can cloud the picture of how much is actually paid for biosimilars vs originator products, and Cigna did not provide actual figures on how much it expects to save.

The competitive pricing pressure from biosimilars has the potential to reduce drug spending by at least $225 billion by 2031, Miller said, citing an Evernorth analysis of drug price data that factored in not just the 20 biosimilars already on the market but also biosimilars that may arrive based on pending patent expirations for some key biologic originator products.

To qualify for the $500 debit card, patients enrolled in Cigna plans would have to switch to a biosimilar or another preferred medication.

“The shared savings program serves as a down payment on the future promise of biosimilars. At a time when many people are having to make difficult decisions related to how to afford their medications, this program will offer some direct financial relief and position customers and their employers to recognize greater long-term cost savings,” Miller said.

Cigna said it will push biosimilar forms of infliximab onto the preferred list and reward patients who make the switch. 

Cigna Offers Patients $500 Debit Card to Switch to Biosimilars

“Pay-for-delay” settlements between originator companies and biosimilar developers have a bad reputation that may not be wholly deserved, said an intellectual property attorney at the American Conference Institute’s 12th summit on Biosimilars & Innovator Biologics.

These agreements are now reviewed by the Federal Trade Commission (FTC), and there is evidence that they are better structured in recent years and play a constructive role in allowing competitor drugs to come to market sooner, said Karin A. Hessler, assistant general counsel for the Association for Accessible Medicines.

The FTC gets a copy of every single settlement agreement that occurs…and they put out a yearly report analyzing settlement agreements, and what has come out of the last 2 yearly reports that the FDC has issued is that Activis has been highly effective in policing these agreements.

Panelists also discussed recent changes to the Purple Book manual of patent information on biologics and various legislative developments that are intended to improve the competitiveness of the US biologics market.

Much alarm has been raised about settlements between originator and biosimilar developers that involve an exchange of royalties or agreements not to enter certain markets before a certain time. In exchange for these agreements, biosimilar companies may avoid costly litigation battles and bring their products to market sooner.

Hessler said an important 2013 Supreme Court decision, 

, clarified when reverse payment patent settlements (pay for delay) are in fact acceptable and this, she said, has led to a gradual improvement in the quality of such agreements, such that pay-for-delay deals are in many cases playing a constructive role in facilitating patient access to lower-cost medicine.

“The FTC gets a copy of every single settlement agreement that occurs…and they put out a yearly report analyzing settlement agreements, and what has come out of the last 2 yearly reports that the FDC has issued is that 

 has been highly effective in policing these agreements,” Hessler said.

Quoting from the December 2020 FTC report, Hessler stated that despite a high number of such settlements, “those that include the types of reverse payments that are likely to be anticompetitive remain very low.”

 a step further by strengthening the test for anticompetitiveness, Hessler said. Under the proposed Preserve Access to Affordable Generics and Biosimilars Act, if there are both a payment of “anything of value” from the originator company to the biosimilar company, such as “an exclusive license,” and any delay in market entry, “even by a day,” there’s a presumption of anticompetitiveness that both parties would have to overcome with compelling evidence that theirs is not an anticompetitive deal.

More pending legislation that is concerning is the Protecting Consumer Access to Generic Drugs Act of 2021, and this, too, hinges on the “anything of value” and “exclusive license” measures of unfairness, Hessler said. This is problematic, she said, because licenses are a necessary tool of business, especially when allowing another party to have use of patented intellectual property, and without such licenses, the settlement process could grind to a halt.

“I think when you’re a party looking at settling, you want to make sure you do it right, and you don’t want to have to be in a grey area where you’re not clear something can or cannot be included,” she said. “I think it’s very important to have predictability. These settlement agreements in some ways have gotten an unfair reputation. They can expedite generic and biosimilar entry by many years. I think there’s some belief that there’s somehow an extension of the patent term that’s occurring here, when what you’re really having is an acceleration relative to the expiration of the patent where generics and biosimilars are coming in early.”

The Purple Book Continuity Act, signed into law in December 2020, improved the amount of patent information available on originator brand products, to make it easier for biosimilar developers to understand where they might infringe on originator company patents.

Hans Sauer, general counsel and vice president of the Biotechnology Innovation Organization, said this act also expanded the information available on original licensing dates for originator products. "This makes it clear when the 12-year automatic product exclusivities begin for originator drugs. If you went to the Purple Book last year, you would have seen that the FDA listed the genuine date of first licensure only for a small number of biologic products,” Sauer said.

Also, “the bill clarifies that these determinations [of first licensure date] are to be made early in the process, and certainly, there’s a big stack of existing reference biologics for which such a determination hadn’t been made. Every product will have a note attached to it as to when its data exclusivity expires,” Sauer said.

Sauer also noted that much information about product patents that was previously not public will be available now, and not in a dusty tome, but in a convenient, searchable FDA website format.

“I think we’ll have a much better understanding across the board of the patents that are being talked about when there is a ‘patent dance’,” Sauer said in reference to the patent information exchange when originators and biosimilar companies face off during the FDA product approval review.

The equivalent to the Purple Book in the generic drugs world is the Orange Book, and in this the patent listings are more complete, noted Hessler.

With the Purple Book, patents are disclosed only as they become relevant to individual biosimilar applications, so the first biosimilar applicant for a particular drug type will find the Purple Book information less complete than the second or third biosimilar applicant. And even for subsequent applicants, the patent information already available may be irrelevant, Hessler noted.

“There’s obviously a situation where different biosimilar applicants may use different manufacturing processes, so the relevant patents that are listed [in the Purple Book] may just not be applicable for the second biosimilar applicant,” she said.

For biosimilar developers in 2020, the FDA worked hard to clarify its guidance, said David E. Korn, vice president of Intellectual Property and Law for PhRMA. One key regulatory development was a shift toward approving insulins and certain other biologics under the Biologics Price Competition and Innovation Act, which created a pathway to streamline the approval of competitive biologics agents, Korn noted. Some of these biologics will end up serving as originator drugs upon which copy drugs are based, he said.

“Even products such as insulins that were approved under a [section] 505(b)(2) application now are 351(k) products that can even be reference products, so the potential pool of reference products got larger through the transition.”

In April 2021 the Advancing Education of Biosimilars Act was signed into law. This provided for educational material to be published by HHS to enable health care providers to understand biosimilar benefits, safety, and conditions for approval. “Overall, this is a well-intentioned and beneficial piece of legislation that we’re going to see implemented by the FDA over the course of this year,” according to Sauer.

Pay-for-delay settlements between drug companies are better regulated than in the past and are in danger of being overregulated, one panelist said. 


Pharmaceutical Pay-for-Delay Settlements "Have a Good Side"

 for the bevacizumab biosimilar Byvasda in combination with the PD-1 inhibitor sintilimab (Tyvyt) for the first-line treatment of patients with advanced hepatocellular carcinoma (HCC).

Byvasda was developed by Innovent Biologics and sintilimab was developed by Innovent and Eli Lilly. A supplemental new drug application is under review with China’s National Medical Products Administration for the therapy combination.

The open-label ORIENT-32 study randomized patients 2:1 to the sintilimab-bevacizumab biosimilar combination (n = 380) or sorafenib (n = 191). Patients in the combination arm received intravenous sintilimab (200 mg every 3 weeks) plus intravenous bevacizumab biosimilar (15 mg/kg every 3 weeks). The sorafenib dosage was 400 mg orally twice daily.

At a median follow-up of 10 months, the independent radiological review committee–assessed median progression-free survival (PFS) was 4.6 months (95% CI, 4.1-5.7) for patients in the combination arm vs 2.8 months (95% CI, 2.7-3.2) for the sorafenib group (HR, 0.56; 95% CI, 0.46-0.70; 

Median overall survival (OS) was significantly longer for patients in the combination arm vs the sorafenib group: median not reached (95% CI, not reached-not reached) vs 10.4 months (95% CI, 8.5-not reached; HR 0.57, 95% CI, 0.43-0.75; 

Investigators said the most common grade 3/4 treatment related adverse events (TRAEs) were hypertension (14% of the sintilimab-bevacizumab biosimilar group vs 6% of the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 12%, respectively).

Serious adverse events were noted in 32% of patients in the combination arm vs 19% of patients in the sorafenib group. TRAEs leading to death occurred in 6 (2%) and 2 (1%) patients in the combination vs sorafenib groups, respectively.

“Sintilimab in combination with bevacizumab biosimilar [Byvasda] showed significant improvements in OS and PFS compared with sorafenib in the first-line treatment of Chinese patients with unresectable, hepatitis B virus [HBV]-associated HCC, with no new safety signals,” the investigators said.

In the safety and activity lead-in portion of the trial (n = 24), ≥ grade 3 TRAEs occurred in 7 (29%) patients.

"ORIENT-32 is the first large-scale study to show the benefit of first-line treatment in HBV-associated HCC with combination immunotherapy,” said lead author Fan Jia, MD, of Zhongshan Hospital of Fudan University, Shanghai, China.

Byvasda was approved in China in June 2020. Sintilimab is 

 in China and a biologics license application for the agent was accepted for review by the FDA in May 2021.

Investigators report survival data for the bevacizumab biosimilar Byvasda with sintilimab (Tyvyt) in hepatitis B virus–associated advanced hepatocellular carcinoma (HCC). 