More Confirmation that Payers Will Cover Beyond the Skinny Label

Since the conception of the biosimilar regulatory pathway in 2010, the term extrapolation has caused confusion and angst for many health system stakeholders. Would the Food and Drug Administration (FDA) approve a biosimilar for all of the reference product’s autoimmune indications, for example, if its clinical studies were in one or two indications only? Mostly, the answer has been yes, with a couple of notable exceptions. We covered this topic back in 2019; since then, Amgen’s rituximab biosimilar was approved, which bridges the rheumatoid arthritis and oncology indications, and the impending adalimumab biosimilar launches have become clearer.

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With Amgen’s launch of Riabni® in January 2021, one of the three rituximab biosimilars is approved for all of Rituxan®’s oncology indications and autoimmune indications. None of the adalimumab biosimilars are approved for every single Humira® indication; however, they are approved for the vast majority. In the upcoming case of denosumab, will FDA grant approval for use in Prolia®’s indications (osteoporosis) as well as co-branded Xgeva®’s (oncology-related indications)? Stay tuned on that one.

Jeffrey Casberg, MS, RPh

According to Jeffrey Casberg, MS, RPh, and Leslie Fish, PharmD, both Senior Vice President of Clinical Pharmacy at IPD Analytics, the approval of these so-called “skinny” labels is generally limited by biosimilar manufacturers’ old nemesis, patents. Generally, a drug maker will file patents on additional indications (one at a time) well after the initial composition-of-matter patents are filed. This means, each indication-based patent will expire at sequential dates. “A biosimilar can launch without all the indications,” said Dr. Casberg at the May Asembia meeting in Las Vegas, “if some of the patents on the indication are not yet expired.” Furthermore, agreements to waive patent litigation between biosimilar and reference manufacturers can allow the launch of a biosimilar but without the full slate of indications.

Drs. Casberg and Fish emphasized that this is not related to any clinical or chemical deficiency in the biosimilar. It is simply a legal barrier to full use of the product. The biosimilar has been approved by the FDA to be an acceptable drug equivalent to the reference agent, and as such would be expected to result in the same clinical outcomes. That’s the basis for extrapolation. The implication is that the clinical outcomes for a biosimilar when used in unapproved indications would also be equivalent to those of the reference product.

Payers seemingly understand this point. “More than 50% of insurers are allowing the use of biosimilars for all indications even if the biosimilar does not have the indication,” they said in their presentation. This aligns well with our own continuing market research with payers, with the latest performed more recently to monitor the 2023 adalimumab launches. We’ve found that in more than 70% of cases, medical and pharmacy executives emphasize that if a biosimilar’s cost is significantly less than the reference product, it would make little sense to aggressively manage its use to the skinny label or extrapolated indications only. If the unapproved indication required a different delivery route or formulation, this would not be true. On the other hand, several payers have stated in our research that they will not require special administrative processes to utilize less-expensive biosimilars in the constellation of autoimmune indications.

Adalimumab biosimilars have pretty much the same set of indications, with the exclusion of those that are still patent protected (specifically hidradenitis suppurativa and noninfectious uveitis, which make up a small portion of Humira prescriptions). If a biosimilar is listed as a preferred product on the plan’s formulary, and the prescriber would like to offer adalimumab to a patient with hidradenitis suppurativa, would the plan require the doctor’s office to request Humira use for this specific patient? Not likely. It is just additional administrative work for both, and the biosimilar in this case would still cost less, without any expected difference in outcome.

As Drs. Casberg and Fish said, “This is a legal issue, not a clinical one.”

Competition Squeezes Coherus’ Pegfilgrastim Revenues: Big Expectations for its On-Body Injector

Coherus Biosciences thinks it will be able to amp up its Udenyca® sales in 2023, by introducing a competitor on-body injector to Neulasta OnPro®.

Stay at home with Neulasta® (pegfilgrastim) Onpro® | Neulasta® Onpro®

According to IQVIA data, Amgen’s Neulasta OnPro currently has about half of the marketshare for the entire pegfilgrastim category. Biosimilars hold approximately 30% of the total uptake, and Coherus’ product is still leading the biosimilar pack. However, in the first quarter of 2022, Coherus registered a 28% drop in net revenue compared with the same quarter last year. This was, according to the company, “primarily due to a decrease in the number of units of Udenyca sold as well as a lower net realized price due to increased competition.” This is unsurprising, based on previous reporting and statements from the company.

Competing with OnPro could unlock greater sales over the long term. Coherus itself believes that this is a $1 billion market opportunity, with little or no competition from the other pegfilgrastim biosimilar manufacturers. Coherus has been working on its on-body injector formulation for some time. In October 2021, the company released the positive results of a pharmacokinetic and pharmacodynamic study of its on-body injector form of Udenyca versus its original prefilled syringe. This phase 1 study likely formed the basis of its “prior approval supplement” to the Udenyca biologic licensing application (BLA), which is awaiting approval with the Food and Drug Administration (FDA). The company is expecting to be able to launch this delivery form in 2023.

Assuming it is successful in its endeavor, this will be the first time a biosimilar will be introduced in two very different delivery forms. Celltrion has marketed in other countries, and is seeking approval from the FDA, a subcutaneous formulation of infliximab (sold in the US as Inflectra®), in addition to the conventional infusible form. However, the reference product (Remicade®) was not available in an injectable form, so the FDA must consider Celltrion’s new product approval as somewhat different from a standard 351(k) application or prior approval supplement to a biosimilar BLA. Instead, FDA required Celltrion to submit its subcutaneous form as a new drug or “bio-better.” This meant new phase 3 trials, the last of which will have initial results in July 2022. Based on this date, an FDA decision may be possible in 2023. Of further interest, the phase 3 trials involve patients with Crohn’s disease and ulcerative colitis. Based on these results, will the FDA grant Celltrion extrapolation to the other indications of Inflectra’s infusible form, like it can do for other biosimilars?

Fortunately for Coherus, no phase 3 trials are needed for its investigational on-body injector. Both Neulasta and OnPro have been proven to offer equivalent clinical efficacy, as well as pharmacologic properties. The only questions are when the launch will occur, and how quickly Coherus can erode OnPro’s marketshare.

In related biosimilar news…Coherus Biosciences also announced that it was discontinuing development of its bevacizumab biosimilar candidate CHS-305, which the company said was delayed due to COVID. This marks the end of a partnership with Innovent Biologics, which was initially announced in January 2020. Coherus also decided to drop the development of its aflibercept biosimilar, with partner Junshi Biosciences. Junshi continues to work with Coherus on other investigational biologics.

Will a Pharmacy Benefit Design Someday Include a Biosimilar Tier? Not Likely, and Here’s Why

For the first several years of biosimilar research, approvals, and launches, we wondered aloud whether payers could potentially introduce a “biosimilar tier,” a low cost–sharing tier that would entice patients to switch to less-expensive biosimilars by using the low-copay carrot approach. This was discussed with patient advocates as well as payers.

Plans covering biosimilars, specifically Medicare prescription drug plans (PDPs), had not encouraged biosimilar adoption through lower cost sharing. In 2021, Socal and colleagues published the results of a survey of Medicare PDPs (admittedly, infused infliximab is almost exclusively covered under the medical benefit or Medicare Part B). They found that between 2016 and 2018, virtually none of the PDPs offered infliximab biosimilars under a lower cost-sharing tier; nearly all covered biosimilars at parity to the reference product Remicade®.

The researchers concluded, “Formulary placement of infliximab biologic and biosimilars in Medicare Part D is not optimized to generate cost savings for the Medicare program and beneficiaries, whose cost sharing is often based on the drug’s list price. The Medicare program should provide incentives for PDPs to expand biosimilar coverage.”

This conclusion was seconded by the well-publicized March report from the HHS Inspector General’s office, which estimated the savings opportunity from Medicare for encouraging biosimilar use. However, the report stated that in 2019, Medicare beneficiaries overall paid on average less out of pocket for biosimilars than for reference pegfilgrastim, filgrastim, infliximab, and epoetin-alfa. Both reports are limited by data that are 3+ years old, a very long time in the biosimilar arena, considering recent adoption rates and launches and availability of several newer oncology biosimilars.

A couple of biosimilars drugs (outside of adalimumab) that may be covered under the pharmacy benefit will be available in the next couple of years. This includes ustekinumab (Stelara®). Interestingly, this drug is currently under tier 2 in UnitedHealthcare’s Advantage formulary and in Cigna’s three-tier formulary. If the biosimilar is already offered at a tier 2 copay (i.e., $50-$75 per prescription), how much lower could biosimilar tier cost sharing be? Could plans waive cost sharing under this benefit? Perhaps exclude them from any drug deductibles? Even put them into a generic drug tier?

Plans that prefer biosimilars tend to make them available with sufficiently low cost-sharing tiers. Even if they are not preferred, they may be listed at parity on tier 3, which still represents far lower out-of-pocket costs than if it was covered on a specialty tier.

Furthermore, insulins, arguably the most heavily used of the biosimilar medications, will not be part of a biosimilar tier. Individual states are mandating out-of-pocket cost limits, and CivicRx is planning to set the cost of its insulin glargine at a very low wholesale acquisition cost; health systems and payers may opt for generic-level cost sharing for this product rather than a higher-cost biosimilar tier.

And we should not forget that a high proportion of costly medications today are subject to manufacturers’ copay cards, which minimize patient out-of-pocket costs, at least for the first year of therapy. This will likely be the case with the launches of new adalimumab biosimilars. Their manufacturers will come to market with patient services offerings that mimic those of AbbVie.

All of these factors may make talk of a biosimilar tier moot. If payers and PBMs do want to encourage the use of biosimilar agents on the pharmacy benefit, they will have to keep patient cost sharing affordable (irrespective of the products’ costs to the plan or PBM). Judging by the trend today, payers do seem to understand that.

And Then There Were None: Celltrion Signs AbbVie Licensing Deal for Its Adalimumab Biosimilar CT-P17

South Korea–based Celltrion Healthcare announced on April 27 that it has completed its negotiations with AbbVie and that it expects to launch its biosimilar at the same time as the rest of the field—in July 2023. It was the last remaining Abbvie licensing deal to be completed for the Humira® biosimilars.

Celltrion’s biosimilar, CT-P17, is currently undergoing review by the FDA. Celltrion submitted its 351(k) application in November 2020, which should result in an FDA decision before the end of this year. The drug is sold under the brand name Yuflyma® in Canada, the EU, and in Asia. This adalimumab biosimilar is a high-concentration, citrate-free agent.

The licensing agreement signed by Celltrion is not expected to vary substantially from the arrangements inked by the other eight adalimumab biosimilar makers vying for US marketshare in 2023. That is, royalties will be paid to AbbVie on sales of their individual biosimilars, while all ongoing patent litigation is dropped by the maker of Humira. As many as seven biosimilar manufacturers intend to launch their products in July 2023. Amgen will launch in January, with a 6-month lead on the rest,  and Samsung Bioepis will launch in June 2023.

It seems that Celltrion will not seek a marketing partner for the new product; it markets this drug in Canada with internal personnel. Currently, Teva is the company’s marketing partner for its approved oncology biosimilars Truxima® and Herzuma® (and Teva is already contracted to market Alvotech’s adalimumab biosimilar entry). It is also engaged with Pfizer to market its infliximab biosimilar Inflectra® (and Pfizer is preparing to launch its own adalimumab biosimilar in July 2023 called Abrilada®). In the adalimumab category, it looks like all the potential biosimilar marketing partners have already been asked to the dance.

Preliminary Phase 3 Study Data Looking Good for Amgen’s Ustekinumab Biosimilar

Amgen announced on April 18 that its 563-patient study of ABP 654’s efficacy and safety is not demonstrating any clinically meaningful differences compared with the reference product Stelara® in moderate-to-severe plaque psoriasis. The study completion date is scheduled for early June 2022, whereas a multiswitch study is scheduled for completion March 2023.

Based on the confirmation of the successful noninferiority results, Amgen may file for approval with the FDA as early as Q4 of this year, which could result in an FDA decision in late 2023. This would put Amgen’s ABP 654 on roughly the same track as Formycon’s FYB202 and Celltrion’s CT-P43 as they vie for first biosimilar launch in the $6 billion US Stelara market. The principal Stelara patent expires in September 2023.

In other biosimilar news…Amgen has emerged with a patent victory for its branded product Neupogen®. The US Court of Appeals has rendered its decision in an old case, involving a Patent Trial and Appeal Board (PTAB) judgment in favor of Apotex. However, Apotex long ago gave up on its quest to bring a filgrastim biosimilar to the US market.

Hopefully, the confusion over the identity of Viatris’ insulin glargine biosimilars won’t become a real issue. The company announced a recall of one batch of its unbranded insulin glargine (insulin glargine-yfgn) 100 U/mL injection, because of missing drug labels on some vials. Since Semglee® also carries the same -yfgn designation, this could be a source of some questions. The recall does not involve Semglee® vials, only the authorized biosimilar form, according to Viatris.

Amneal Scores FDA Approval of Alymsys®, a Biosimilar of Bevacizumab

On March 1, Amneal announced that it had entered the biosimilar market with the FDA approval of its filgrastim biosimilar (Releuko®). On April 14, the company announced another major step on its biosimilar journey: the approval of its second biosimilar, a new version of bevacizumab.

Dubbed Alymsys (bevacizumab-maly), the new agent is the third Avastin® biosimilar approved in the US. The biosimilar was developed by mAbxience, it will be marketed in the US by Amneal.

Alymsys is approved for the treatment of:

  • Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy (first- or second-line treatment)
  • Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy (second-line treatment for patients who have progressed on a first-line bevacizumab-containing regimen)
  • Non-squamous non–small cell lung cancer, in combination with carboplatin and paclitaxel (as first-line therapy)
  • Recurrent glioblastoma in adults
  • Metastatic renal cell carcinoma, in combination with interferon alfa
  • Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan
  • Epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with paclitaxel

Amneal is awaiting word on its third biosimilar entry, a pegfilgrastim, which is presently awaiting FDA approval. No word is presently available on the launch date for Alymsys.

A Profile on Lesser-Known Player in the Biosimilar Space: Prestige Biopharma

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight an interesting company based in Singapore.

Founded in 2015, Prestige Biopharma has production facilities in South Korea and a research center in Cambridge, Massachusetts. Lisa Park, one of the founders, is listed as its CEO (interestingly, its website does not disclose the leadership team). The company is focused on biosimilar development and a couple of innovative products. Prestige has also been involved with COVID-19 vaccine production over the last year or so.

Why you may be hearing more about this company: Prestige has one product approaching the registration phase: a trastuzumab biosimilar (HD201) that may be submitted for FDA approval by Q3 2022. HD201 has already been submitted to the EMA for review, after completion of its phase 3 trial last month. In addition, its bevacizumab biosimilar HD204 is currently in late-stage clinical study (to be completed in December 2022).  An adalimumab biosimilar in entering phase 1 trial.

However, Prestige’s website lists nine other biosimilars in preclinical stages, covering products like aflibercept, denosumab, eculizumab, nivolumab, pembrolizumab, pertuzumab, and ipilimumab. Interestingly, they are also engaged in preclinical research for a natalizumab biosimilar (reference drug Tysabri®), which is also being a target of Sandoz. The one difference is that Sandoz is seeking approval for the multiple sclerosis indication (which accounts for about 90% of Tysabri® utilization), and Prestige notes that the Crohn’s disease indication is its focus.

Biosimilar Bytes

What do nanomedicines and biosimilars have in common? Not much, one might think. At the 2022 annual meeting of the Academy of Managed Care Pharmacy, we learned a new term: nanosimilars. John Hertig, PharmD, MS, Associate Professor at Butler University described nanomedicines as complex, non-biologic pharmaceuticals that range up to 1,000 nm in size. They include the liposomal drug formulations and were first available in the middle of the 20th Century. These drugs, like biologics and biosimilars, are highly dependent on the manufacturing process—any changes can affect the critical characteristics of the medicine. Copies of nanomedicines (> 50 are approved in the US), like biosimilars, are inexact, and phase 4 outcomes trials are required to confirmed the equivalency of these nanosimilars to the originator product.

Formycon AG purchased the operational assets of Bioeq, part of its partnership with ATHOS in Europe. Formycon and Bioeq are working with Coherus Biosciences to commercialize a biosimilar version of ranibizumab (FYB 201), which is awaiting FDA approval. Formycon and Bioeq are also collaborating on a biosimilar version of ustekinumab (FYB 202). The phase 3 study for FYB 202 should be concluding presently.

Alvotech and AbbVie have signed an agreement that clears all patent litigation for marketing its adalimumab biosimilar in Europe. On March 8, Alvotech and AbbVie agreed to a royalty-based licensing agreement that allows Alvotech to launch AVT02 in the US in July 2023, contingent of course on FDA approval.

A new study by European researchers affirmed the safety and efficacy of switching among the reference product infliximab (Remicade®), and the biosimilars Inflectra® and Renflexis® in patients with inflammatory bowel disease. A total of 176 patients were assigned to one of three groups: (1) patients who underwent two infliximab switches, from the reference product to one biosimilar and then to the other biosimilar; (2) patients who switched from one biosimilar to the other; and (3) patients who switched between Remicade and one biosimilar. The researchers found no significant differences, 12 months after the final switch, with regard to clinical remission, laboratory results (e.g., C-reactive protein levels), treatment persistence, or in safety parameters, regardless of infliximab switch group. The authors noted that all patients were in remission at the time of study entry (switching was not attempted during a clinical relapse or flare-up of disease).

A Conversation With Sarah Ikenberry and Laura Pincock, Food and Drug Administration on Biosimilar Education in Health Sciences Schools

The issues relating to biosimilar misinformation have spurred calls for improving the level of knowledge of practicing healthcare providers. This effort must also seek to educate tomorrow’s healthcare providers about biosimilars today. BR&R spoke with two of the key forces behind the FDA’s important initiative to provide biosimilar education at the schools of medicine, nursing, and pharmacy.  

Laura Pincock is a Health Communications and Education Specialist and Sarah Ikenberry is a Senior Communication Advisor for the Office of Therapeutic Biologics and Biosimilars, Center for Evaluation and Research, Food and Drug Administration.

Sarah Ikenberry and Captain Laura Pincock

BR&R: We’ve been talking as a community for some time about countering the amount of biosimilar disinformation and the type of disinformation that is available. What are your own views on the FDA’s project to bring biosimilar education to the medical, nursing, and pharmacy schools?

Sarah Ikenberry: It seemed to me that the FDA was taking a proactive approach to educating healthcare providers and other audiences about biosimilars and interchangeable products.

We’ve conducted research projects to understand what people know about biosimilars and what they don’t appreciate. We used that to inform the educational materials that we’ve developed. In a nutshell, that’s how we approached it.

BR&R: Was the impetus more to help future healthcare professionals understand the difference between an interchangeable biosimilar and a conventional biosimilar, or the more basic difference between a biosimilar and a reference product? Did you find that there was much more need for information on the former or the latter?

Ikenberry: There’s a definite lack of understanding about the differences between a biosimilar and interchangeable agent. We’re trying to address that in the best ways we can.

From Landscape Research to Toolkit

BR&R: Please tell us about the steps involved in bringing this project to completion.

Laura Pincock: First, we wanted to get a baseline understanding of what’s being taught. Second, we attempted to evaluate what needs to be taught about biosimilars. And third, we needed to develop the kind of materials that would be best for the faculty to use in teaching these topics.

Ikenberry: We started by contacting those schools’ accrediting organizations, before speaking with the schools themselves, to pick their brain about how to go about this project. Our contractor, Booz Allen, conducted interviews with a small sample of deans and faculty at medical nursing, and pharmacy schools to better understand their main education needs. We wanted to address the unmet needs of the faculty with educational materials they can utilize in their own teachings.

Pincock: We also spoke to our colleagues internally at FDA and considered the research that had already been available.

We didn’t interview students though; we assumed they know little about biosimilars before being exposed to teaching materials.

BR&R: One of the things that we heard in 2019–2020 during our own initial investigations with schools of pharmacy and medicine was that their curriculums are so packed already. We heard a lot of comments like, “How can we fit or utilize this in the current curriculum?” Educators were looking for other ways to incorporate biosimilar learning into the students’ experience.

A couple of schools had developed an elective symposium to provide upwards of four hours of vital but basic information on biosimilars. This was not part of the formal curriculum, however. Did the individual schools you spoke with indicate that one type of approach would be better than another?

Pincock: We found that the method of educating students about biosimilars is not at all consistent. Pharmacy, physician, physician assistant, and nursing students receive biosimilar information at different times in their training. This may be as part of the didactic work, coursework, or educational module about the FDA regulation or manufacturing. In some cases, the schools themselves may not provide any education on biosimilars; students may not be exposed to biosimilar information until they begin rotations or even start their clinical practice.

As a result, we wanted to create a variety of materials that could be used in different stages of the students’ training and in a variety of mediums. In the digital world today, some students learn more effectively through videos; some would prefer to read more comprehensive, printed materials; and some would prefer just the facts. Making this information available in a variety of ways provides faculty with the flexibility to incorporate these topics into their own curriculum.

We published the curriculum toolkit in December 2021, and it’s available on our website (https://www.fda.gov/drugs/biosimilars/curriculum-materials-health-care-degree-programs-biosimilars). It’s the culmination of all of these efforts.

We will now begin to add additional materials and updating the current information. We’re already starting to look forward and how we can improve on the toolkit. We’re doing presentations and trying to increase awareness and understanding of the materials.

BR&R: The key here seems to be flexibility.

Pincock: And you’re right about the density of the curriculum. There is just so much information these schools need to teach, and there’s no clear consensus on the best time to teach it. That’s why we developed two levels of education in the toolkit: (1) basic, high-level information that is probably more appropriate for newer students and (2) in-depth materials, based in more regulation and science for healthcare professionals who are near the end of their training or about to start clinical practice. Those Level 2 materials are specifically for people who will be working with pharmacists or need to know real-world concepts on how biosimilars or interchangeables will be used, prescribed, dispensed, and monitored.

Biosimilar Education for Clinicians

BR&R: The timing of the toolkit’s completion has coincided a very interesting period for biosimilars: The designation of the first interchangeable biosimilars, and the approval of the first biosimilars for ophthalmologic use, and we’re on course now for next year’s launch of adalimumab biosimilars and interchangeables. It seems the toolkit’s release couldn’t come at a better time. What’s the next steps?

Pincock: This particular project has targeted student education. We will also be working with Medscape on developing and updating new continuing education programs for practicing healthcare professionals.

Ikenberry: It’s very hard you know with the different ways that these products are administered (e.g., in providers’ offices, hospitals, or outpatient facilities) and delivered by specialty pharmacies. Other than insulin, you can’t obtain these medicines at a community pharmacy.

We have other general educational materials that we’ve been putting out to try to provide information about interchangeability and the fact that biosimilars are just as safe and effective as the reference product.

BR&R: Is the FDA planning to hold any webinars or individual sessions targeted for plans or health systems (other than working with Medscape), discussing the availability of the toolkit?

Pincock: I think that’s the goal. We did disseminate information about the toolkit very widely when it was made available in December, sending it out to deans of the various schools of pharmacy, medicine, and nursing that worked with us in addition to the ones that didn’t. We also disseminated it to other associations that work with or represent healthcare professionals who use biosimilars. Sarah Yim (the Director of FDA’s Office of Therapeutic Biologics and Biosimilars) has been actively presenting on the need for biosimilar education and discussed the materials as well.

The materials are primarily geared for student learning, but the Medscape webinars will be for practicing clinicians. We really think we’ll be able to reach the folks that need it.

It Will Be Difficult to Move Away from Phase 3 Studies for Biosimilar Approvals

The Food and Drug Administration has repeatedly emphasized that biosimilar approvals are based on the “totality of evidence.” However, the agency has emphasized that analytical comparability of biosimilars with reference products comprises by far the most important share of the evidence considered. Phase 3 clinical trial evidence contributes less to biosimilar approval decision making, as opposed to approval decisions for reference biologics.

Views in the biosimilar industry are evolving with the science and the accumulating evidence. And there is a lot of it: not only the European experience consisting of tens of millions of patient-days of use but the US approval of 34 biosimilars and 21 launches.

juliana Reed

At the Festival of Biologics USA 2022 meeting, several thought leaders advocated for a further deemphasis on large-scale, phase 3 clinical trials for biosimilar approval. These late-stage studies have not revealed significant safety or efficacy issues with biosimilars, and their cost is thought to be a considerable obstacle to new manufacturers entering the biosimilar competition for existing and future products. Not only are these studies, encompassing hundreds of patients and dozens of study centers, expensive to administer, but the cost of obtaining reference product samples for study can cost prohibitive amounts.

Hillel Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, explained that the “analytical tools available today are far better at characterizing these molecules than they were 20 years ago. This includes carbohydrate analysis, and the ability to build cell lines to get precisely the molecule that you want.” In other words, the science has moved forward. “Today, the clinical and efficacy tools are much less specific than what we can achieve with the analytic studies,” he said. We should consider modifying “our regulatory expectations based on the current scientific capability.”

David Charles, MD

Juliana Reed, Executive Director of the Biosimilars Forum, agreed, saying “We should not have the expectation that every biosimilar should have a clinical trial.” The information about the molecule that is obtained through analytics is so detailed today. “We know that the reference product is efficacious, and we know its safety profile. The analytics tell us that the biosimilar is a very close copy.” The inference is, why are we spending resources to confirm what is fairly obvious?

The FDA has now approved a few biosimilars that had not been the subject of a phase 3 trial (e.g., Udenyca®, Nyvepria®, Nivestym®). These have been generally in drug categories where other biosimilars were already approved. Even in those circumstances, phase 1 and/or phase 2 study data were available.

At the conference, David Charles, MD, Medical Director and Founder of the Alliance for Patient Access, and a physician specializing in the treatment of movement disorders, said that “biologics have been a part of my practice since 1995.” He was strongly against eliminating clinical trial evidence for the approval of biosimilars: “The notion of bringing a biosimilar to market without a clinical trial would be a nonstarter for me. These are complex disease states. I feel that clinical trials remain important.” He does believe “the FDA is by and large getting it right—adapting as the science is progressing. But at the end of day, safety and efficacy is most important to me.” Eliminating these phase 3 trials will undermine physician and patient confidence, Dr. Charles stated.  

Although I don’t agree with Dr. Charles’ position, he does has a point. Several years after approval of infliximab biosimilars, gastroenterologists and rheumatologists remain well behind oncologists in their acceptance of biosimilars. This will likely change rapidly after the introduction of adalimumab biosimilars, and payers will move to force utilization changes through their coverage policies. For specialists who have not had biosimilar experience to date, introducing new biosimilars to their practice may certainly run into barriers of confidence, without phase 3 trial experience. This can only slow provider adoption.

Emanuela Lacana, PhD

This seems to be a debate of the mind versus the gut. The mind understands that if analytic characterization says that the biosimilar is essentially the same as the reference product, the gut still wants data it can digest.

In the meantime, Emanuela Lacana, PhD, Deputy Director, Office of Therapeutic Biologics and Biosimilars, FDA, confirmed that “eliminating human clinical trials is not likely, because they provide a level of comfort to practitioners.”

It is worthy to note that biosimilar makers seeking to bring a product to market need to decide on the need for a phase 3 trial several years before actually filing a new 351(k) application. The FDA’s clinical development program is attempting to play a strong proactive role, consulting with these manufacturers on the potential need for phase 3 trials. If that expensive clinical trial barrier will be put aside for new reference drug categories tomorrow, the FDA will likely have to put a stake in the ground today.