Articles

The FDA clarified a number of concerns surrounding the appropriate procedures for industry to apply for interchangeability status.

FDA Issues Draft Guidance Q&A on Biosimilar Interchangeability Submission Requirements

Tony Hagen is senior managing editor for The Center for Biosimilars

The wearable injector has a failure rate that adds hospitalization costs; therefore, biosimilar pegfilgrastim may hold cost advantages, investigators conclude. 

Investigators: Biosimilar Pegfilgrastim Has Advantages Over Wearable Injector

The Songdo district of Incheon, Republic of Korea, is rapidly becoming a major biopharmaceuticals production center. 

Celltrion Relies on Domestic Construction Amid the Pandemic

In November, the Supreme Court heard arguments on the Affordable Care Act, Europe fired up its efforts to create a more biosimilar-friendly environment, and Genentech fought to protect its bevacizumab franchise.

Biosimilar Legal Roundup: November 2020

The merger of Pfizer's Upjohn division and Mylan has created a biosimilars powerhouse with global reach. 

Newly Created Viatris Joins the Biosimilars Forum

Each is an abbreviation of the biosimilar brand name.

Suffixes are deliberately random and nonsensical.

They signify key differences between biosimilars and originator brands.

Physicians prefer using suffixes rather than brand names.

For background reading on this topic, click 

Check out the results from our last poll:

Biosimilar suffixes were intended to help with pharmacovigilance, but they are not widely understood. 

Poll: How Much Do You Know About Biosimilar Suffixes?

The biosimilar market in the United States has had a difficult start since the launch of the first biosimilar in 2015, facing many legal, regulatory, and policy barriers that stall market entry for many FDA approved products, slow down adoption rates and price drops, and discourage physician and patient use of biosimilars. Although some may look at the market and see only its flaws, some experts have hope for the market to change and flourish.

We sat down with Marcus Neubauer, MD, chief medical officer of The US Oncology Network, Kathryn Tong, MBA, vice president of Payer, Pharmacy, Analytics & Transformation for McKesson, and Tommy Pourmahram, vice president of Multi-Source & Analytics for McKesson to discuss some of the factors currently holding back US biosimilar adoption, what reforms are needed to improve it, and what stakeholders can do to help.

To learn more about biosimilar barriers, click 

To learn more about the US Oncology Network, click 

Podcasts

We sat down with a trio of experts to discuss the factors currently impacting biosimilar adoption, what reforms are needed to improve it, and what stakeholders can do to help.

Not So Different: A Trio of Experts on What Needs to Change to Boost Biosimilar Adoption

 positive phase 3 clinical study data for its bevacizumab biosimilar candidate (HLX04). The trial compared the biosimilar with reference bevacizumab (Avastin) in combination with the chemotherapy regimens Xelox and mFolfox6 as a first-line treatment for metastatic colorectal cancer (mCRC).

Investigators said HLX04 demonstrated efficacy, safety, and immunogenicity equivalence to Avastin. Potential oncology indications for HLX04, besides colorectal cancer, include advanced, metastatic, or recurrent non–small cell lung cancer.

The trial, HLX04-mCRC03, was a multicenter, randomized, double-blind, parallel controlled study that randomized patients 1:1 to the biosimilar candidate (n = 338) or reference product (n = 337) delivered intravenously (7.5 mg/kg every 3 weeks when combined with XELOX or 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary end point was progression-free survival (PFS) at week 36.

PFS was 46.4% in the HLX04 group and 50.7% for the reference cohort. Henlius said the group difference was –4.2% and fell within predefined equivalence margins, demonstrating biosimilarity. Investigators said there was no statistically significant difference between the biosimilar candidate and reference drugs in terms of overall survival, PFS, objective response rate, time to response, or duration of response. Safety and immunogenicity profiles also were equivalent.

“The results of the phase 3 study demonstrated the equivalence in efficacy between HLX04 and reference bevacizumab with similar safety and immunogenicity profiles as first-line treatment for mCRC patients. HLX04 will provide an alternative treatment option for cancer patients as a potential biosimilar candidate,” the company said.

Henlius also aims to obtain indications for ophthalmic diseases such as wet age-related macular degeneration and diabetic retinopathy.

Biosimilar developer Celltrion Group said it has completed enrollment of 327 patients for a coronavirus disease 2019 (COVID-19) drug candidate phase 2 clinical trial. If results are positive, the company aims to apply for emergency use authorization from the Korean Ministry of Food and Drug Safety.

In preclinical studies, the agent, CT-P59, demonstrated a 100-fold 

 in viral load of SARS-CoV-2, the virus that causes COVID-19, as well as a reduction in lung inflammation.

The phase 2, randomized, double-blind, controlled trial is evaluating CT-P59 in patients with mild and moderate symptoms of COVID-19 in 3 cohorts: placebo, low concentration dose, and high concentration dose. “Results from the trial are expected in the coming weeks,” said Sang Joon Lee, senior executive vice president of Celltrion.

A Shanghai Henlius Biotech study demonstrates equivalence for its bevacizumab candidate, and Celltrion moves forward with a trial for a SARS-CoV-2 candidate. 

Henlius, Celltrion Group Report Product Development Advances

The European Commission (EC), the group that authorizes medicines for the European Union, has issued a 

for emerging from the coronavirus disease 2019 (COVID-19) pandemic with a stronger, more competitive health care industry that is more supportive of the uptake of biosimilars and generics.

The EC “pharmastrategy” issued this week outlines a myriad of goals, such as achieving a more competitive system that does not discourage innovation or turn biosimilar and generic producers away, developing a deeper understanding of pharmaceutical supply chain issues so that uncertainties spawned by the pandemic can be managed more effectively the next time, and improving country-by-country procurement of medicines by strengthening the competitive bidding system.

“Though we are experiencing a period of rapid change and innovation, many patients do not benefit from that innovation, because medicines are either unaffordable or unavailable. And there is greater awareness of the need to ensure that our use of pharmaceuticals is sustainable,” the EC said.

The blueprint also calls for stepping up efforts to develop new antimicrobials and antibiotics (a subclass of antimicrobials) and impose regulations that encourage more safe and sensible use of these medicines. This will include greater use of existing regulatory tools to combat growing resistance to these medicines.

In response to the statement, Medicines for Europe, a trade association of pharmaceutical manufacturers, called upon the EC to work especially hard to develop a marketplace that promotes access to biosimilars, generics, and other “value-added” drugs.

“Often in Europe, patients can only fully access the medicines they need when the off-patent version becomes available. Barriers to off-patent medicines use must be removed,” the group said in a 

COVID-19 has had “a very serious impact on Europe,” and although the European Union’s strengths in responding have been showcased during the pandemic, its vulnerabilities have been “thrown into sharp focus,” the EC said. There have been problems with data availability, medicine supply, and manufacturing capacity.

“The conclusion of advance purchase agreements for vaccines is nevertheless an example of effective cooperation between public and regulatory authorities, industry, and civil society organizations,” the EC said.

But because of access bottlenecks in various markets, innovative therapies do not always reach patients, the EC said. “Companies are not obliged to market a medicine in all EU countries.” 

This might happen because of national pricing and payment policy, population size, health system organization, or relative wealth factors country by country, the EC suggested. The blueprint included recognition of a critical lack of transparency on research costs and necessary return on investment, which each factor into a company's decision to enter or refrain from entering a market.  

“Drawing on this and wider experience, the commission will review the system of incentives,” the EC said.

In tandem with this, the EC said it will consider “targeted policies” for beefing up generic and biosimilar competition. “This may include further clarifying the provisions for the conduct of trials on patented products to support generic and biosimilar marketing authorization applications.”

The EC said it intends to buttress these efforts with “enforcement” of rules on competition, noting that “originator companies sometimes implement strategies to hinder the entry or expansion of the more affordable medicines of their generic and biosimilar competitors and that such strategies may require competition law scrutiny.”

Reforming the competitive landscape is not a one-way street, the EC said. It called upon health systems and private companies to make use of an “innovation partnership” tender system that allows for cooperative agreements on development, manufacturing, and subsequent purchase of medicines.

“Certain conditions…such as the absence of automatic substitution rules for biologicals, can create market barriers,” the EC said. “This lack of competition thus inhibits price savings once innovative products lose their market exclusivities. The commission will take this into account in the review of the pharmaceutical legislation, to see how sound competition can best be fostered, leading to a downward effect on prices of medicines.”

In a recent white paper, Medicines for Europe described numerous intellectual property hurdles that constitute barriers to entry for biosimilars and generics. To read the story, click 

The European Commission (EC) said it will take the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic and build a better marketplace for generics and biosimilars.

EC Eyes Enhancements for a Post–COVID-19 Marketplace

With the pandemic raging, things are done differently in the biosimilars sphere these days, Christopher Hansung Ko, president and CEO of Samsung Bioepis, said in an interview at the Financial Times Global Pharmaceutical and Biotechnology Conference 2020.

For one, regulators seem motivated to move applications along swiftly, he said. “Regulators are acting much faster than they ever have. I’ve never seen clinical trials being approved this quickly. And their willingness to engage and look at the interim results…has been welcoming sight. I hope that regulators will continue this type of approach post-pandemic. Then we’ll see a much greater number of products being approved in a short period of time.”

On the other hand, the pressure is on to make supply chains watertight. This has meant building in redundant systems to ensure that if there’s a breakdown in process or supply flow, the goods can get to market, he said.

“The pandemic taught us that we need to be better prepared as a company and as an industry. Redundancies have been built into vendor selection, raw material production, and shipping methods.

“Prior to the pandemic, it was taken for granted that this much duplication was unnecessary, but we realized that we needed to become experts at those details and be vigilant about it,” Ko said. It was also necessary to become more involved with suppliers to understand their operations and COVID-19 precautions “to make sure that they had enough staffing and that people were being trained as backup.”

This also goes for ensuring the success of clinical trials, he said. Those who sponsor and run clinical trials want to be sure that sufficient quantities of experimental drugs are going to be available.

“It’s still very difficult with current restrictions and with the second wave that’s hitting Europe and the United States,” he said. “These are sort of the last hopes for the sick patients—to be on clinical trials to get affordable care. We have to constantly communicate to investigators, nurses, and patients to give them the assurance that the investigational product will be delivered so they can plan ahead.”

Samsung Bioepis is an Incheon, Republic of Korea–based joint venture between Samsung Biologics and Biogen. Predominantly a biosimilars company, Samsung Bioepis has 5 drug products launched in Europe and 2 in the United States.

Biosimilars represent a means of expanding access to medicines during coronavirus disease 2019 (COVID-19) because as they are introduced, they enable health care institutions to save money and use these savings to expand other types of care, Ko said.

“All countries globally are concerned about the rising health care cost. There’s a limited amount of money they can spend on health care, but innovations have to happen, and there’s built-up pressure that can no longer accommodate new innovation, which makes biosimilars the pressure valve,” he said.

And the savings can be enormous, Ko said. This is partly because modern biologic manufacturing processes have evolved and even current systems of producing biosimilars may be far more efficient than ones originally used for creating the reference drugs.

“We’re using state-of-the-art, cutting-edge technology with process innovations. We’re able to deliver our products at much lower costs. In some territories, we’ve seen biosimilar prices discounted 80% to the originator.” The savings potential is significant, he said.

Despite all the precautions to ensure production continuity during the pandemic, the resurgence of this virus across the globe is reason for concern, Ko said. “The number of patients diagnosed is far greater than in the first wave, earlier in 2020. I’m concerned about people’s movement and people’s inability to go to the doctor’s office and get new prescriptions filled and receive a diagnosis,” he said.

Also, pandemic limitations on movement are reshaping product development, Ko said. “Traditionally, all oncology products were infused, so this required infusion chairs at clinics, and those are becoming a much more costly option for health care systems. Now, they’re trying to use subcutaneous formulations that patients can administer at home. We will continue to see the migration from an infusion setting to a self-care type of subcutaneous, auto-injectable space or some other format that allows a patient to administer outside the clinic,” he said.

Christopher Hansung Ko, PhD, president and CEO of biosimilars company Samsung Bioepis, discusses innovations and precautions the pandemic has brought to the field of biosimilars.

Samsung Bioepis CEO Discusses the Pandemic's Effect on Biosimilars

Bio-Thera Solutions of Guangzhou, China, has filed a marketing authorization application to the European Medicines Agency for approval of BAT1706, an investigational biosimilar candidate that references Avastin. 

The company said it hopes to obtain authorization for all indications of the reference product in the European Union, Iceland, Norway, and Leichtenstein. 

The application marks the first "ex-China" application for biosimilar approval, or approval application for a drug developed in China for marketing abroad. 

"Bio-Thera intends to bring its pipeline of biosimilars and innovative therapies to patients around the world and this submission is an important step for extending the global reach of BAT1706," said Shengfeng Li, founder and CEO.

Bevacizumab targets vascular endothelial growth factor (VEGF) by blocking the binding of VEGF to its receptor and thereby reducing vascularization that supports the development of tumors. 

The reference product is approved in Europe for colon and rectum cancer; metastatic breast cancer; non–small cell lung cancer; renal cell caner; epithelial ovarian, fallopian tube, and primary peritoneal cancer; and cervical cancer. 

Bio-Thera also intends to seek regulatory approval in the United States, and a biologics license application filing is anticipated before the end of 2020, the company said. 

The company has one already marketed biosimilar, Qletli, an adalimumab biosimilar, which has been authorized for distribution in China.

This marks the first time a Chinese company has filed application for marketing of a biosimilar outside of China. Bio-Thera of Guangzhou, China, said a US application is pending.

Bio-Thera Solutions Files for EU Bevacizumab Approval

The Center for Biosimilars® (CfB):I'm Tony Hagen, senior editor for The Center for Biosimilars®. Today, we're talking with Jorge Garcia, assistant vice president of the Oncology Service Line at Baptist Health South Florida and also a member of the Association of Community Cancer Centers' Board of Trustees. Garcia explained how Baptist Health gave pharmacists latitude to issue biosimilars to patients to reduce administrative complications and save money. He also discussed strategies used by innovator companies to keep biosimilars off the market and the effect this is having on patient access.

Reimbursement is a significant barrier [for biosimilars]. At Baptist Health, you've managed to increase biosimilar use by putting the pharmacy in charge. Can you describe how you achieved that and what you learned from this experience?

Absolutely. So, I think for a successful biosimilar implementation, one of the key components is that for every patient and every administration, you have to [check] out the benefits. And we do that, again, for every patient on every administration, because the patient's benefits could change throughout the course of the therapy. We see that a lot with Medicaid patients and older patients that have life changing events and other things of that nature.

So, prior to our new process, our authorization team would go ahead and get an authorization for whatever the doctor was prescribing, and when they were not successful getting an authorization, they would have to contact the provider again and have them write for a different product based on what that health plan required. And that process was convoluted. The physicians, sometimes, would not get that message on time, or it would take them some time to update the system to the new orders. And this would be, obviously, frustrating to the authorization team and very stressful as the date of treatment got closer and closer and we still didn't have the right orders for that patient.

What we did to eliminate that is we, today, follow a facility preference approach where when we review biosimilars in P&T [pharmacy and therapeutics committees], we provide our authorization team with our facility preferred products. So, regardless of what the prescriber prescribes, our authorization team will always try to get an authorization for our preferred product. And if they're not successful getting an authorization for our preferred product, then they tailor to whatever the health plan provides. And they document that in the EMR [electronic medical record]. When our pharmacists are verifying that product under the product dispensation, we see the notes from the authorization team, saying specifically which product the health plan approved, and our pharmacists are able to independently switch to the product that the patient has benefits for.

What that did in turn is it eliminated the providers from being a part of that workflow. We do have an automatic substitution policy that we had in place way before biosimilars existed. And we just added our biosimilars to that policy. And of course, we have provided input about what goes into that our substitution policy that basically allows us to independently make those changes without having to consult with the providers every single time.

This has been a huge satisfier for the providers, because what they want is for the patients to get the drug. They know that a lot of this is heavily payer dictated and they don't want to be involved in the logistical piece of it. All they want to know is that their patient is going to get the drug that they intended. Our authorization team is also not having to constantly be contacting the providers to have things changed. So, this has really been a best practice that has been transformational in our ability to manage the day-to-day, where we leave very little room for error there, because we do that benefits investigation on a dose-by-dose basis, obviously, patient-by-patient.

CfB: So, a doctor will not prescribe by brand; he or she will prescribe by the generic name of the product, say trastuzumab or bevacizumab. And your team will decide on whether you can get preauthorization for the biosimilar that goes by that name or whether you have to use a brand product or something else, is that correct?

That is exactly correct. And if, in any way, the provider wants to keep the brand names, they have the ability to write ”medically necessary,” just like we would write in a prescription. But we don't see that very often at all.

CfB: To make a system like this work in harmony, you need to overcome certain complexities. You may need to educate all the stakeholders in your institution. Can you describe how you accomplished this and how you smoothed the way for a process like this?

Absolutely. I think when we think about a biosimilar implementation, a few stakeholders come to mind. Obviously, the pharmacy, nursing, and the providers. But there's more. There are the IT [information technology] teams. Typically, those IT teams have a long agenda of priorities, so the biosimilar agenda has to fit into those. They’re an important stakeholder to keep in mind. Also, with the type of capabilities that they can provide to support this process, I mentioned that we moved our program to document it in our EMR and that required a simple interface that IT was able to do for us. And we also have drop-down options for multiple products, and you just have to work with your IT team to understand what kind of capabilities they can lend to you to make this process successful.

But it also requires including the registration team for some products, like pegfilgrastim. What product you choose dictates whether the patient is going to get treatment that day or the day after. So, [the registration department] has to understand that to be able to register patients appropriately. And then, the business office, the authorization team, and others. In my experience, those clusters of teams can vary within one organization. So, I will have to meet with a group of folks if I do a biosimilar implementation in an outpatient facility. If I am doing the same biosimilar implementation in an inpatient facility, there is a different nursing team, a different pharmacy team, and a different authorization team. So, you have those clusters of teams that are going to work closest to that site of care to be able to have it be successful.

CfB: We've discussed the pegfilgrastim differentiation and how an innovative product can take market share away from biosimilars, just as Neulasta Onpro has done. Patent thickets around adalimumab [Humira], have prevented biosimilars from reaching the US market. How are these things affecting the success and the sustainability of the biosimilar market?

Yeah, there's so much that goes into this. And I really appreciate this question. But I think the important thing to recognize is that biosimilar companies take a lot of risk when they decide to pursue a biosimilar. We know that there is no patent protection for biosimilars. So, you could have any number of players in that market when you decide to pursue biosimilar adalimumab. You know that many other companies may develop a biosimilar and they will play in that space. You’re never guaranteed a market share of that, if at all. We need to recognize that component.

In the space of adalimumab specifically, we know this is the one biologic with the highest cost at a global scale. Here in our country, we see that that product has lifted the entire patent exclusivity period. And we still cannot pursue biosimilar options due to patent litigations and other things until 2023. That's concerning. We know, per the FDA website, if we go today, we know that there are several adalimumab biosimilar programs that have been completed and approved. And those companies are standing by until 2023 to be able to give us a biosimilar option.

And again, I think, in our industry, we all understand the full patent exclusivity period and how necessary that is to support innovation and innovative companies. That's not the argument here. The concern is more so that once those products have gone through the entire path and exclusivity period, how many more years in addition to that do we provide exclusive market access? That's a concern. I think it is less of a concern in other countries that have completely different patent protection laws, and I think that is why Europe has been so successful and we have seen a lot more market penetration of biosimilars in general.

One other point to make here, specifically in the case of adalimumab and specifically as it relates to the level of risk that pharmaceutical companies have when they pursue biosimilars, is that by 2023 when biosimilars for adalimumab may be able to enter the market, the standard of care may be something different. AbbVie [Humira's manufacturer] itself has a couple of new products that are demonstrating better outcomes. And so, when we get to 2023, again, the standard of care may no longer be adalimumab or the biosimilar version of that, but it may be something else. However, these companies have already invested a ton of resources to get their product studied and approved. So, again, lots of risks are involved when it comes to pursuing a biosimilar.

CfB: A recent report by Amgen was very positive on the health of the biosimilar market, and they described rising market share in a number of the 7 different basic drug categories for which biosimilars have been approved. But then if you talk to other people, such as consultants and so forth who are trying to open up those corridors to biosimilar access, they are very discouraged. And they say that the market is not very healthy at all. Depending on who you speak to, it's a great market or it's a very sour market.

Absolutely, and what we see is that a number of biosimilar development programs have actually been dropped by multiple companies. Obviously, companies try to have their intel on this, and they assess, through the development period, if it's still worth the risk that they are taking based on the evolving market. In the case of adalimumab, like I talked about before, clinicaltrials.gov is listing a number of studies just trying to assess outcomes with adalimumab compared to all other options. So, depending on where those studies go, again, by 2023, the recommendations may be very different from what they are today.

CfB: Yeah. And, of course, if the recommendations for your products aren’t good, this could be devastating for these 9 companies that are lined up to bring adalimumab products to the market.

CfB: And caught in the middle of this issue are the patients. They'd like cheaper medication, but they've got to wait, in case of adalimumab, wait until 2023 to get a cheaper product. So, alongside access to lower-cost products goes affordability. So, you cannot expand the number of patients being treated if you can’t lower the price. Can you discuss these issues?

Absolutely. So, a couple of angles that we could take with that question there. I think, especially looking at European models, when you have access to products at a lower cost, you can get more units of that product to make available to more patients. And so, with biosimilars you do look at increased access. It is believed that that access is going to translate into better outcomes. We have ongoing studies trying to paint the full picture there. I think again, Europe is a little bit more advanced that than we are with that regard.

But in models, when we think of the patient out-of-pocket [costs] we think of the typical insured patient, but the reality is that we have patients that are underinsured or completely uninsured. In our geographical area of South Florida, we have patients that are self-pay and we have patients that are international patients [who have to] cover a lot of those expenses directly. So, this means different things to many of those patients' categories. But to your point, in the case of adalimumab, they're not having a biosimilar option at a fraction of the cost the way that they do for other biologics that there is a biosimilar available for.

And I really think, from a provider standpoint, our goal is to make sure that we have a parity approach, so that we present that provider and that patient with options, and based on their situation, they can decide financially what is the best choice. And we do see in our experience that patients are highly sensitive to their financial responsibility, even when it may come down to just their out-of-pocket responsibility. So, when you have that discussion with the patient, and you educate them, in our experience, we see a lot of patients favor biosimilar options.

In our practice, we have a class—a chemotherapy biotherapy class—that every patient must undergo before they begin treatment. We talk to them about biosimilars. I cannot give you any examples of a single patient that have reached out and said, "I am not comfortable with the biosimilar options," and we've had hundreds and hundreds of patients.

So, again, I think patients as stakeholders in understanding the clinical part of the discussion, which is done by a nurse navigator, and the financial part, the out-of-pocket with our financial navigators, tend to be very supportive of biosimilars. But we have to be able to present them with that opportunity. And that's what it boils down to. Sometimes due to a payer restriction, we cannot present them with a biosimilar opportunity or some other times due to just no access in the marketplace, like in the case of adalimumab. Patients are not able to drive that benefit today.

CfB: Providers are often concerned about using biosimilars and they prefer to look at clinical data rather than the type of evidence that the FDA relies upon for biosimilar approval. Can you discuss this issue here? Why can't doctors be persuaded on pharmacokinetics and other types of evidence rather than going for comparative data, which is not considered all that reliable?

Yeah, but I think we have to really look at the approval process for biosimilars, which is not to reestablish the safety and efficacy of the compound because that has already been done by the innovator company. The goal is really to demonstrate biosimilarity and or interchangeability. And so, we do rely heavily on analytical studies. But we also do clinical studies for pharmacokinetics [PK], pharmacodynamics [PD], and immunogenicity. And I think that's [where there are] misconceptions. I think some believe that there are no clinical studies at all. But we know that that PK, PD, and immunogenicity studies are there to support every FDA approval.

I think the other component to keep in mind is that if those studies do not yield sufficient evidence, that pathway definitely does call for a phase 3 clinical trial; in this case, it will be more so a confirmatory trial to just try to resolve remaining uncertainty.

Now, the way things have been going here in the US, the FDA has been able to gather enough evidence just by having the PK ,PD, and immunogenicity studies and not requiring those phase 3 studies. But we are seeing that some companies are taking the initiative to have more of a phase 3 type of study design, or, we have not seen it yet, but again, the FDA can request that study if they deem that necessary.

I think what we have to keep in mind here is that balance. The goal of biosimilars is to try to bring product options to the market at the lowest feasible cost. And if we have very robust confirmatory trials, that can get very, very expensive. We already talked here about how there is no path and exclusivity for biosimilar companies. So, they will be doing all of these trials pretty much like the innovator companies did to bring their product into the market with no guarantee of product utilization because there's no patent exclusivity. So, the model itself is not sustainable by just having multiple companies do all of these studies at the phase 3 level.

We followed a different approach looking at most sensitive patient populations and looking at extrapolation and other methodologies, to, again, show that there is biosimilarity. The safety and efficacy of the compound has already been proven.

And I guess, just to close with this question, today, we do have 5 years of pharmacovigilance of biosimilars being exposed to large patient populations in things like extrapolated indications or patients that were interchanged because their insurance required them to change between products. And so far, we are not seeing any indications to pharmacovigilance that there is any clinically meaningful difference in terms of safety or efficacy. Furthermore, beyond the use of biosimilars in our country, we know Europe has another 6 years on top of our 5 years of experience. And in both of these 2 markets that I follow closely, we have not seen any incidents of any biosimilar that have been removed from the market due to a safety or efficacy concern.

Videos

Jorge Garcia, PharmD, MS, MHA, MBA, assistant vice president of the System Oncology Pharmacy Service Line at Baptist Health South Florida, discussed how Baptist Health increases biosimilar use and how innovator companies fight to avoid biosimilar competition.

Part 2: Jorge Garcia on Giving Pharmacists Latitude to Switch to Biosimilars

Considering Alvotech doesn't have any biosimilars approved, some may question why the company is signing biosimilar distribution deals all over the globe. The answer, according to Joseph E. McClellan, PhD, MBA, Alvotech's chief scientific officer, is that the Reykjavik, Iceland-based company aims to obtain regulatory approvals for multiple products almost simultaneously in multiple countries and then launch.

The worldwide market for biologic originator drugs exceeds $300 billion and is growing at a 10% clip each year. “We’re in the earlier stages of a long-term expansion for the global biosimilars market,” he said in a recent presentation on the company’s expansion strategy and the challenges of entering markets with different regulatory standards for biosimilar approval.

On November 24, 2020, Alvotech announced a 

 with CCHT Biopharmaceutical of Changchun, China, and Yangtze River Pharmaceutical Group, of Taizhou, China, to commercialize 8 biosimilars in China. The deal follows on the heels of other announced partnerships for distribution in North America, South America, Europe, the South Pacific, Africa, and the Middle East. Alvotech has biosimilars in development for autoimmune diseases, ophthalmology, and oncology.

Regulatory standards differ from country to country. While regulators in Europe and the United States tend to hold that comparative clinical efficacy trials are not of significant value in demonstrating biosimilarity, this is not the case elsewhere, where animal and in-human studies of biosimilars may be required to complete the package of evidence required for consideration of approval.

Analytical, pharmacokinetic (PK) studies are the foundation of biosimilar approvals in the United States, but when it comes to clinical studies—although they already were performed for originator drugs—the goal for some regulatory authorities may be an added level of reassurance, McClellan said.

“In vitro tests for looking at function are much more sensitive, and as you progress from binding assays and cell binding assays, and function cell assays, your sensitivity decreases for demonstrating similarity," he said. "Of course, as you move into in vivo animal models and human clinical trials, the clinical relevance is deemed to be more significant. It’s that balance. If you’re going to do an in vivo animal model, what are you trying to solve there. It’s likely it’s about providing the confidence about the safety of the molecule."

China tends to require animal studies as a condition of doing human clinical studies, as well as the use of locally sourced reference product for the comparator drugs. It would be easier if the reference product required for testing could be standardized across the globe, McClelland said. “How do you include China when you want to use 1 product for your clinical studies, whether PK or a comparative patient study? It’s an interesting challenge.”

Such requirements also make it difficult for Alvotech to execute on another of its strategic goals, which is to perform PK similarity and clinical confirmatory studies almost in parallel to one another to speed up development and get to regulatory approval faster. With regional partnerships across the globe, “We also have that commitment to ensure that we can develop our biosimilars in a speedy manner,” McClellan said.

China is very strict about requiring that nonclinical studies be performed before clinical studies, he added.

Smoothing out the obstacles in this quest means that Alvotech has to engage with regulatory authorities from individual countries early in the development process to shape the biosimilar development project and understand local priorities for approval, McClellan said.

Japan, also one of the world’s largest markets for biologics, presents a different challenge. That country’s regulatory authority requires that subjects of Japanese origin be included in clinical studies.

Another Alvotech goal is to develop commercial scale operations for its product development efforts. The company seeks to develop biosimilars for approvals in all indications of the reference products in the markets it enters.

At its headquarters in Reykjavik, Alvotech has a 140,000-square-foot facility for manufacturing and product development. It also has a production center under construction in Changchun that will have the capacity for producing 2.5 million “patient treatments” a year. The project is a partnership with the Changchun High & New Technology Industry Group.

The company has research and development operations in Julich and Hanover, Germany; Virginia; and Zurich, Switzerland.

Joseph E. McClellan, PhD, MBA, discussed navigation of regulatory hurdles as the company continues its quest to line up distribution partnership deals across the globe. 

Alvotech Scientific Officer Describes Company's Global Biosimilars Strategy

Minute differences between biosimilars and reference products are not considered “clinically meaningful,” but these differences are exploitable when it comes to addressing allergies related to originator products, said a panelist at the National Policy and Advocacy Summit on Biologics.

In the United States, some physicians and patients remain wary of using biosimilars, even though the FDA certifies them as equivalent to originators on safety and clinical efficacy. Because they are made from living organisms, biologics—whether reference drugs or biosimilars—may differ slightly from one manufactured batch to another, but strict process controls keep these differences within tight margins of allowed variation.

Panelist Jeffrey VanDeusen, MD, PhD, explained that these subtle differences can actually be an asset in treating certain patients. “Instead of perhaps 1 therapy that is able to target a pathway, we've got multiple medications that are different enough that if a patient may be allergic to that medicine, now we have different options to offer that patient.”

VanDeusen, medical director of the James Cancer Network and an assistant professor of medicine at the Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, gave an example of one of his current patients with cancer who developed an allergy to originator trastuzumab (Herceptin) and was able to continue treatment using a biosimilar.

“Ten years ago, I would have had to stop the medication for her. Now, I can continue that medicine….I can effectively continue to control her disease without relying on new or different medicines,” he said.

VanDeusen discussed other ways biologics have improved treatment options in the oncology space. He said that biologics, especially growth factors, have extended the lives of patients much longer than before.

“We are able to target specific proteins in cancer cells or pathways in cancer cells, and this has allowed us to either control or even completely eliminate cancers, whereas before, we would just have drugs that would perhaps delay the growth for a while. Now, instead of weeks to months, we can change that to years or even a normal lifespan,” said VanDeusen.

Further, “as we get more and more sophisticated in our understanding of the immune system and how to help it defeat cancer, we are going to see biologics play a larger role as these agents are used in that in that type of fight.”

During the panel, VanDeusen mentioned that delays in diagnostic testing, with genomic sequencing or proteomics, could prevent patients from receiving a biologic treatment in a timely fashion. Without diagnostic testing, which can be expensive, physicians are not able to prescribe biologic treatments.

“For oncologists, when a procedure is done as a diagnostic test—for example, a liver biopsy—often there is a 2-week cool-off period, where we have to wait before additional testing can be ordered on the specimen. And in that time, the patient’s disease can grow. And that is hard for both the oncologist and the patient,” said VanDeusen.

Additionally, VanDeusen said that a lack of health coverage can delay diagnostic sequencing even further to where the patient’s symptoms may worsen, allowing the cancer to spread. In some cases, he said, delays may allow a patient’s disease to worsen to the point that therapy is no longer an option.

The National Policy and Advocacy Summit on Biologics was a virtual conference on November 18, 2020, hosted by Biologics Prescribers Collaborative, the Institute for Patient Access, and the Alliance for Patient Access.

Minute differences between biosimilars and reference products are not considered “clinically meaningful,” but these differences are exploitable when it comes to addressing allergies related to originator products.

Providers Exploit Minor Differences Between Innovator Drugs and Biosimilars

Investigators at the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine hope to reproduce results of a successful phase 2B trial of GP2 peptide/G-CSF in patients with HER2-equivocal or -positive breast cancer who have received a standard course of trastuzumab, reference or biosimilar form, following surgery.

GP2 plus GM-CSF is believed to stimulate a tumor-specific cytotoxic immune system response against HER2-positive cancer cells. Phase 2 studies help determine whether a drug shows any activity against the target disease and assist with setting optimal dosing. Phase 3 trials assess the value of a drug in a clinical setting.

In the retrospective, placebo-controlled phase 2B trial, completed in 2018, after a median 5 years of follow-up, no cancer recurrences were observed in the adjuvant setting among patients with HER2-equivocal or -positive breast cancer who received the full course of 6 primary intradermal injections over the initial 6 months (

 = .0338), according to subgroup analysis.

In that earlier study, the immune response, as measured by local skin tests and immunological assays, was potent, investigators said. In addition, among 138 patients who have received GP2 over 4 clinical trials, the treatment was well tolerated, with no serious adverse events attributable to the therapy, investigators said.

In the phase 3 trial, investigators hope to reproduce those results in preventing recurrence of HER2-equivocal or -positive breast cancer both post surgery and following an initial year of treatment with trastuzumab, including biosimilars.

GP2 is an investigational drug being developed by Greenwich LifeSciences of Stafford, Texas. Lead investigator and Greenwich LifeSciences CEO Snehal Patel pointed to the value of GP2 if it proves to be a reliable tool in reducing HER2-positive breast cancer recurrence. “We are addressing a potential market of up to $5 billion in a disease that affects 1 in 8 women, who if recur, will likely face metastatic breast cancer,” he said.

Patel SS, McWilliams DB, Fischette CT, et al. A prospective, randomized, multicenter, double-blinded, placebo-controlled phase III trial of the HER2/neupeptide GP2 + GM-CSF versus bacteriostatic saline/WFI placebo as adjuvant therapy after any trastuzumab-based therapy in HER2-positive women with operable breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract OT-13-03. https://www.sabcs.org/Portals/SABCS2016/2020%20SABCS/Final%20PDF%20Docs%20111620_All%20PDF%20File%20No%20Embargoed%20Abstracts.pdf?ver=2020-11-17-095626-250

GP2 peptide/G-CSF in HER2-equivocal and -positive breast cancer has shown promise.