Tony Hagen is senior managing editor for The Center for Biosimilars

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Articles

American Conference Institute: Summit on Biosimilars & Innovator Biologics

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

ACI Panelists Discuss Misaligned Incentives in the Biosimilars Market

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Congress of the European Crohn's and Colitis Organisation (ECCO)

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

Adalimumab Biosimilar Transition Studies Reported at ECCO'21 Congress

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

A model of rituximab use that involved transitioning a portion of patients to intravenous rituximab biosimilar (Truxima) from a subcutaneous originator rituximab (Rituxan) formulation demonstrated savings of $2359 to $8186 per patient with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL), investigators reported at this year's American Society of Clinical Oncology meeting.

Truxima is a CD20-directed monoclonal antibody and was the first of 3 rituximab biosimilars approved in the United States.

Investigators based their savings analysis on a 5-million-member insured population (Medicare) in which 972 patients would be treated for NHL or CLL during a 1-year span. Of those patients, 49 would receive subcutaneous rituximab/hyaluronidase (SC-R). For purposes of the study, investigators assumed that 25% of the 49 patients (n = 13) would receive intravenous biosimilar treatment (IV-R-BIOSIM).

The 1-year model factored in drug and administration costs and assumed efficacy and safety would be equivalent between the 2 cohorts. For the IV-R-BIOSIM dosing, the investigators assumed body surface area of 1.8m

The objective was to project incremental cost differences between [IV Truxima] and [SC-Rituxan] over 1 year for a hypothetical 5-million-member US healthcare insured (Medicare) population.

They also assumed annual dose counts (with either IV-R-BIOSIM or SC-R) of 10 for untreated follicular lymphoma (FL) with maintenance; 8, untreated FL without maintenance, relapsed/refractory FL, or untreated diffuse large B-cell lymphoma; and 6, CLL. Duration of IV-R-BIOSIM infusion was assumed to be 3 hours. SC-R costs included an initial IV Rituxan dose.

For the 13 patients who received the hypothetical IV-R-BIOSIM dosing, estimated total 1-year savings were $57,864. The investigators said their budget impact model was most sensitive to low or high body surface area dosing and the proportion of patients with CLL.

“These findings demonstrate the potential economic benefits of IV-R-BIOSIM vs SC-R that may result in expanded access to rituximab therapy,” they said.

James E, Trautman H, McBride A, Choudhry A, Thompson S. US budget impact analysis of an intravenous rituximab biosimilar versus subcutaneous rituximab for the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Presented at: ASCO 2021; June 3-7, 2021. Abstract e18821.

ASCO

Sizeable savings per patient with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) were anticipated by a Medicare savings model. 

Budget Model Predicts Savings for Switch to Rituximab Biosimilar in NHL, CLL

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

For patients receiving myelosuppressive chemotherapy for breast and lung cancer, same-day pegfilgrastim to combat febrile neutropenia is safe and effective. 

In real-world studies, the trastuzumab biosimilars Kanjinti and Zedora demonstrate comparable safety vs Herceptin for breast and gastrointestinal cancer. 

The Oncology Care Model lowers use of supportive-care medications and boosts filgrastim biosimilar use.

Oncologists’ use of 3 biosimilars soared from 2019 to 2020. 

Texas Oncology’s automatic biosimilar switching program led to single-month savings of $4 million (21%) among 460 health care practitioners. 

Pegfilgrastim administered on the same day as myelosuppressive chemotherapy to ward off febrile neutropenia (FN) 

 increase the incidence of FN, investigators reported.

The trastuzumab biosimilars Kanjinti and Zedora delivered safety outcomes 

 to those for the originator product (Herceptin) in real-world breast and gastrointestinal cancer treatment settings.

 in the Oncology Care Model concluded that this alternative model of payment does contribute to less use of certain products, such as denosumab, in various types of cancer.

 started slowly and then gathered momentum. The savings may have been why: Costs per biosimilar prescription were lower than the reference product prescription cost by 42.0%, 29.9%, and 89.5% for trastuzumab, rituximab, and bevacizumab, respectively.

 patients to bevacizumab, trastuzumab, and rituximab starting in July 2020 and reported hefty savings per administration: $550 for bevacizumab, $850 for trastuzumab, and $1400 for rituximab.

Diverse findings on biosimilar safety and savings were presented at the American Society for Clinical Oncology (ASCO) 2021 Annual Meeting. 

Poll: What Were the Most Important Biosimilar Findings Presented at ASCO?

“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"

Real-world studies demonstrating comparable safety for trastuzumab biosimilars vs the originator (Herceptin) were presented at the ASCO 2021 Annual Meeting. 

Investigators in Poland said a study of patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer who switched to the trastuzumab biosimilar Kanjinti yielded safety outcomes comparable to those for Herceptin.

“The 12-month follow-up treatment with Kanjinti [demonstrated] an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Kanjinti or Kanjinti combined with pertuzumab, the safety profile was similar to that previously reported in other studies,” investigators said.

Clinicians have been cautious about switching patients to trastuzumab biosimilars because of the paucity of real-world data for these agents, hence the value of conducting this study, investigators said in the abstract presented at 

The observational retrospective study evaluated Kanjinti therapy in patients (N = 195) with HER2+

breast cancer between July 2018 and January 2020.

Investigators said 34 patients received carboplatin, docetaxel pertuzumab, and the trastuzumab biosimilar in the neoadjuvant setting; 99 received Kanjinti as monotherapy or in combination with other cytostatic drugs in the neoadjuvant or adjuvant settings; and 62 received docetaxel, pertuzumab, and the trastuzumab biosimilar in the metastatic setting.

In this population, pertuzumab was used in conjunction with the trastuzumab biosimilar in 49% of patients (32%, first line of palliative treatment; 17%, neoadjuvant settings); 65% of patients with metastatic breast cancer switched to the biosimilar form of trastuzumab; and 37% of patients with early breast cancer switched. “Switching was done at a median of the fourth cycle.”

Investigators said 6 patients experienced a decline in left ventricular ejection faction and no other trastuzumab-related adverse events (AEs) occurred.

In a second real-world trastuzumab biosimilar (Zedora; Mylan/Biocon) Brazilian study, predominantly evaluating patients with HER2+ breast cancer, AEs for Zedora were comparable to those associated with Herceptin.

“The risk benefit remains consistent with the reference safety information and no new safety signals were detected,” investigators wrote. 

Zedora is marketed in the United States under the brand name Ogivri and was 

Investigators evaluated 74 AE reports from 73 female patients with

HER2+ breast cancer and 1 male patient with gastric adenocarcinoma. Among 656 AEs identified in the reports, 588 (89.63%) were nonserious (413 expected, 175 unexpected) and 68 (10.37%) were serious (51 expected, 17 unexpected)

Among the 17 serious unexpected AEs, 13 were not related to trastuzumab therapy and 4 were related to therapy, investigators said. Among the 175 nonserious unexpected AEs, 56 were unrelated to therapy vs 119 related.

The most common AEs, according to system organ classification, were 111 (16.92%) general disorders/administration site conditions, 98 (14.93%) gastrointestinal disorders, and 88 (13.41%) nervous system disorders.

Those included diarrhea (4.11%), fatigue (3.66%), nausea (3.35%), weight decrease (2.74%), and infusion reactions (2.59%).

“The AEs noted in patients with breast cancer and gastric cancer treated with biosimilar trastuzumab were consistent with the known safety profile of trastuzumab,” investigators said. Earlier findings from the study were reported at ASCO annual meetings in 2019 and 2020.

1. Jagiello-Gruszfeld AI, Lemanska I, Brewczynska E, et al. Trastuzumab biosimilar (Kanjinti) in breast cancer patients: one-center retrospective observational study. Presented at: ASCO 2021: June 3-7, 2021. Abstract e13015.

2. Monteiro da Silva A, Watanabe TTWO, Honda E, Yamaguchi J. Biosimilar trastuzumab active post marketing surveillance real world 2020 data update: results from a patient support program for patients under treatment with the first biosimilar trastuzumab approved in Brazil. Presented at: ASCO 2021: June 3-7, 2021. Abstract e14504.

Real-world evidence from Poland and Brazil confirms comparable safety for the trastuzumab biosimilars Kanjinti and Zedora in the breast and gastrointestinal cancer settings.

Safety Findings Are Reported for Trastuzumab Biosimilars

Same-day vs next-day administration of pegfilgrastim as prophylaxis against febrile neutropenia (FN) in patients undergoing myelosuppressive chemotherapy (CTX) shows promise despite preexisting concerns this may increase the incidence of FN, investigators reported in studies of patients with lung and breast cancer presented at the ASCO 2021 Annual Meeting.

With the savings biosimilars afford and in a country emerging from the COVID-19 pandemic, same-day treatment appears to make economic and practical sense, they said.

Findings from a retrospective study at the University of Arizona suggest that for patients with lung cancer, same day treatment with pegfilgrastim “provides a unique opportunity for cancer care without concerns for FN,” investigators wrote.

Guidelines suggest that pegfilgrastim be administered 24 hours after myelosuppressive chemotherapy (CTX), and data from previous studies had not clarified the utility of same-day vs next-day pegfilgrastim use for this class of patients, they said.

They included 114 patients who met the inclusion criteria; 76% (n = 87) of patients had non–small cell lung cancer and 24% (27) had small cell lung cancer. Of those, 52% had stage III/IV cancer and 63% had ECOG status of 0 to 1.

Study authors said 72% of patients had mild FN risk, mean standard deviation absolute neutrophil count at baseline was 5.68, and 384 CTX cycles were received in total.

One patient developed FN after the first cycle of CTX of irinotecan and, across all cycles, 5 patients developed 6 FN episodes.

Two of those patients were on carboplatin etoposide, 1 was on cisplatin etoposide, and 1 on vinorelbine. For the patient who experienced 2 episodes of FN, these occcured following a switch from pemetrexed to irinotecan CTX.

Vraney J, AlRawashdh N, Choi B, Abraham I, McBride A. An institutional evaluation of the safety and efficacy of same-day administration of pegfilgrastim in patients receiving chemotherapy for lung cancer. Presented at: ASCO 2021: June 3-7, 2021. Abstract e18591

In patients with breast cancer, pegfilgrastim biosimilar (Udenyca) administered as prophylaxis for FN on the same day as CTX appears to be safe and effective, investigators wrote. “Previous literature has indicated that pegfilgrastim administration prior to 24 hours post chemotherapy may result in a deepened and prolonged neutropenia due to the increase in circulating granulocytes exposed to chemotherapy.”

Oncologists at Inova Schar Cancer Institute in Fairfax, Virginia, conducted a retrospective chart review of 55 patients treated by 4 medical oncologists in the center’s breast cancer group. They said 16.4% of patients experienced grade 3/4 FN and 10.9% (n = 6) were hospitalized. There were no grade 5 events and FN was not the cause of therapy discontinuation for any of the patients. “Of note, there were no cases of COVID-19 among the 9 patients who had an episode of FN.”

They said 94.5% (n = 52) of patients included in the study received treatment with curative intent and 5.5% (n = 3) had metastatic disease in subsequent lines of therapy.

“Same day pegfilgrastim-cbqv appears to be a safe and effective option in the primary and secondary prophylaxis of FN with myelosuppressive standard of care chemotherapy used in breast cancer treatment,” they concluded.

They cautioned that their study was confined to a relatively small sample of patients and a young age group (median age, 49.1).

“This opens the door to further re-evaluation of same day [Udenyca] administration in other patient populations. In a postpandemic treatment world, this slight change in practice has the potential to reduce patient financial toxicity associated with multiple medical visits, provide an alternative to on-body injector formulations, and ensure treatment adherence,” they said.

Leiva M, Pennisi A, Kiernan Harnden K, Rizzo PC, Mauro LA. The feasibility of same day pegfilgrastim-cbqv administration in breast cancer patients receiving myelosuppressive chemotherapy regimens at a northern Virginia cancer center. Presented at: ASCO 2021: June 3-7, 2021. Abstract e18687

Same-day pegfilgrastim to combat febrile neutropenia in conjunction with myelosuppressive chemotherapy (CTX) is safe, investigators conclude. 

Investigators: Same-Day Pegfilgrastim Is Safe and Effective in Patients Receiving CTX for Breast, Lung Cancer

Celltrion Healthcare reported positive findings from a European Union real-world 

 comparing the company’s rituximab biosimilar (CT-P10, Truxima) with the reference product (Rituxan) in patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL). Results were reported at the European Hematology Association 2021 Virtual Congress.

Celltrion also released real-world data demonstrating comparable safety and effectiveness of CT-P10 rapid infusion.

CT-P10 treatment data were collected during a 30-month observation period. Primary end points included overall survival (OS) and progression-free survival (PFS), and secondary end points included safety profile and CT-P10 treatment pathways.

At the 30-month point, OS was 74% (95% CI, 69.2%-79.1%) and PFS was 67% (95% CI, 61.3%-72.1%) among patients (N = 382) undergoing first-line treatment with CT-P10.

Among enrollees, a complete response (CR) was observed in 82% (n = 312); partial response (PR), 12% (n = 46); no response or stable disease 4% (n = 16); and progressive disease, 2% (n = 8).

CT-P10 tolerability also was reported to be comparable to the reference product. The investigators said 90% (n = 351) of patients reported 1 or more adverse events (AEs), 65% (n = 253) experienced a grade 3 or higher event, and 28% of AEs were reported as “definitely, probably, or possibly related to CT-P10.”

“This is the first multicountry retrospective postapproval study to investigate the effectiveness and safety of CT-P10 treatment in patients with DLBCL in a real-world setting across Europe,” said Mark Bishton, MD, consultant hematologist and a clinical associate professor at the University of Nottingham, School of Medicine, England.

The European Medicines Agency approved CT-P10 for treatment of rheumatoid arthritis and certain blood cancers, including NHL, in 2017. DLBCL accounts for an estimated 30% to 40% of NHL incidence.

“The response rates, survival rates and overall safety profile for CT-P10 appear consistent with those reported for reference rituximab, which could support the use of CT-P10 in combination with chemotherapy as a therapeutic option for DLBCL,” authors of the study wrote.

Discussing the second study, the investigators said rapid infusion of CT-P10 was generally well tolerated, with 10% (n = 20; 95% CI, 6%-15%) of patients experiencing infusion-related reactions (IRRs).

“We are encouraged by the results of the study, as CT-P10 has demonstrated a similar IRR rate to reference rituximab,” said HoUng Kim, PhD, head of the Medical and Marketing Division of Celltrion.

The investigators said most IRRs were grade 1/2 (96%), and the most common of these were fatigue (35%), nausea (30%), and vomiting (15%). Patients achieving CRs and PRs over 6 months of observation were 74% and 22%, respectively.

“The recommended protocol for rituximab infusion in Europe is a slow initial infusion rate with a gradual upward titration. Rapid infusion is often used in subsequent infusions for patients who had no serious complications related to the first infusion,” Kim said.

EHA is the annual meetting for the European Hematology Association.

Postmarketing retrospective studies of the rituximab biosimilar (CT-P10, Truxima) demonstrated comparable safety and efficacy for treatment of diffuse large B-cell lymphoma (DLBCL).

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