On the shelf

By Allison Evans, assistant managing editor

Over the last few years, 12 biosimilars have been approved by the U.S. Food and Drug Administration (FDA), bringing the promise of potentially cheaper treatment options to patients throughout the country. However, after years of sitting idle on the shelf, are they even close to taking off in the United States? Jashin J. Wu, MD, Medical Board member of the National Psoriasis Foundation and a councilor for the International Psoriasis Council, spoke about biosimilars at a dermatology conference a few years ago. “In 2016 and 2017, biosimilars were a hot topic. But in 2018, the conference didn’t even include biosimilars since there’s nothing new happening. The majority of biosimilars that are approved are not available. Once they become commercially available, people will start talking about them again.”

According to a recent report by Avalere Health, the U.S. makes up only 2% of global biosimilar sales, with 87% of the sales taking place in Europe, where the first biosimilar was approved in 2006. Yet, the U.S. is responsible for 59% of reference biologic product sales globally. This suggests the U.S. market may be ripe for biosimilar sales if the conditions are right.

Biosimilars, however, are facing an uphill battle as they begin to enter the U.S. market. Although several biosimilars have been approved by the FDA, litigation, cost-savings considerations, and physician ease-of-use are simply a few of the obstacles that biosimilar manufacturers are encountering.

Status update: FDA approvals

The FDA has made strides in approving new biosimilar treatments: 12 since 2015 — eight of these approvals were gained in 2017 and 2018. According to the Alliance for Safe Biologic Medicines (ASBM), there are at least 240 more biosimilars in the development pipeline.

Six biosimilars have been approved for psoriasis:

adalimumab-adbm (Cyltezo®) and adalimumab-atto (Amjevita®) for adalimumab (Humira®)
infliximab-dyyb (Inflectra®), infliximab-abda (Renflexis®) and infliximab-qbtx (Ixifi®) for infliximab (Remicade®)
etanercept-szzs (Erelzi®) for etanercept (Enbrel®)

As part of the 2010 Affordable Care Act, the Biologics Price Competition and Innovation Act (BPCIA) created a “biosimilar pathway” which outlined the criteria for the FDA to approve biosimilars of interchangeable biologics. “The proposed biosimilar and reference product must have the same presumed mechanism of action, administration route, dosage, and potency to be considered for an abbreviated Biological License Application (BLA),” wrote Paul S. Yamauchi, MD, PhD, a clinical assistant professor at the David Geffen School of Medicine at UCLA, in “A Treatise from the Medical Board of the National Psoriasis Foundation.”

The biosimilar approval process has less emphasis on clinical trial outcomes, and greater attention to the pharmacology of the biosimilar — pharmacokinetics, pharmacodynamics, and immunogenicity, said Dr. Yamauchi. “For originator products, you have to do clinical trials for all approved indications, but for biosimilars, you could do a trial in a few diseases, and if the biologic is approved as a biosimilar, then the information can be extrapolated for other indications approved for the originator product.”

This expedited pathway was created in an attempt to expand patient access and lower health care costs by avoiding duplication of costly clinical trials. “I feel comfortable with extrapolation because it makes sense, as it’s basically the same molecule,” said Dr. Yamauchi. “If the pharmacology of the drug is similar to the reference, then I feel confident that it will perform for the other indications.”

Legal woes

While the FDA has been working to fulfill its promise to streamline biosimilar approvals, only a handful of biosimilars are actually available in the U.S. Infliximab-abda (Renflexis) and infliximab-dyyb (Inflectra) — biosimilars for infliximab (Remicade)— are the only biosimilars commercially available to treat psoriasis and psoriatic arthritis. Two other biosimilars which could be used to treat psoriasis have garnered FDA approval, but are stuck in what could likely become years-long patent disputes.

The first biosimilar to treat psoriasis, Amgen’s adalimumab-atto (Amjevita), a biosimilar for AbbVie’s adalimumab (Humira), was approved in September 2016, but still languishes in the no-man’s-land between FDA approval and commercial availability. Humira had more than 100 patents and shortly before Amgen’s biosimilar gained FDA approval, AbbVie filed a lawsuit for patent infringement. However, Amgen and other potential competitors have filed inter partes review (IPR) in which the Patent Trial and Appeal Board (PTAB) determines the validity of the challenged patents. Three of AbbVie’s patents were invalidated with several others being challenged. One such patent issued in 2014 covered methods of administering anti-TNFa antibodies to treat rheumatoid arthritis. The challenger, Coherus Biosciences Inc., claimed the patent was invalid because the dosage regimen covers “routine optimization of the therapy” that was known by researchers. In May 2017, the PTAB invalidated this patent.

This year, the drug companies reached an agreement that would allow adalimumab-atto to launch in the U.S. in Jan. 31, 2023, and in Europe in October 2018. Under terms of the settlement, all pending patent litigation will end and AbbVie will receive royalties from Amgen.

Similarly, in 2015 a Federal Circuit ruled that it was mandatory for biosimilar sponsors to provide 180-day (six months) notice of commercialization and the notice could only be provided after FDA approval had been granted. However, pharmaceutical manufacturer, Sandoz, argued that the FDA-mandated six-month waiting period was tantamount to an additional six months of exclusivity.

The case made it to the U.S. Supreme Court and, in June 2017, the court unanimously reversed the 2015 decision: Biosimilar companies would not have to wait an additional six months after FDA approval before launching their biosimilar. This case was a win for biosimilar manufacturers as it meant their drugs could enter the market sooner. However, additional challenges remain.

View the AADA’s Position Statement on Generic Therapeutic and Biosimilar Substitution at staging.aad.org/ps-biosimilarsub.

Physician notification and pharmacy substitution

For several decades, brand name and generic prescription drugs have been regulated at the state level. “The AADA started seeing the first legislation on biologic and biosimilar substitution in 2013,” said Lisa Albany, JD, the AADA’s director of state policy. “And now there are 46 states and Puerto Rico that have biosimilar substitution laws in place with the remaining states having filed bills.”

While legislation varies by state, the following are typical features and requirements included in the bills:

A biosimilar must be designated as “interchangeable” by the FDA before it can be substituted. An interchangeable biosimilar must show that the product is expected to produce the same clinical result as the reference product in any given patient, and the risk in terms of safety or efficacy of switching between biological products must be no higher than using the reference product alone.

The prescriber could prevent substitution by writing “dispense as written” or “brand medically necessary.”

The prescriber must be notified of pharmacy substitutions, including a notation in an EHR or other pharmacy record accessible to the prescriber.

Patients must be notified of the substitution or switch, and in some states, patient consent is required before a switch could be made.

The pharmacist and physician must retain records of substituted biologics.

Often, the drug’s cost must be explained and a handful of state laws require the biosimilar to have a lower cost if it is to be substituted.

According to the AADA’s Position Statement on Generic Therapeutic & Biosimilar Substitution, the Academy advocates that the pharmacist notify the prescriber by the time of dispensing (view the position statement at staging.aad.org/ps-biosimilarsub).

Physician notification ranges from 24 hours to, in some states, 10 days. “What we’re seeing most often is three to five business days,” said Albany. “Earlier bills used language like a ‘reasonable amount of time,’ which the AADA did not support because the language was too vague.” While most state laws now specify a time frame for physician notification, the AADA still strongly advocates for physicians to be notified before or as patients receive the prescription, said Albany. “The closest we’ve come is with North Dakota’s legislation, which specifies 24-hour physician notification.”

ROI DOA?

Although the expedited pathway and removal of entry barriers have been helpful in bringing more biosimilars to market, biosimilars have not garnered as much savings as once anticipated. Generics revolutionized the way drugs were sold in the U.S., initially offering deep discounts to branded drugs — as much as 80% to 90%. A few years ago it was thought that biosimilars could do the same, potentially saving the U.S. up to $54 billion over 10 years, according to a RAND report. The savings have been nowhere near those of generics, though. Pfizer, for example, priced its biosimilar infliximab-dyyb (Inflectra) at only a 15% discount to the reference biologic infliximab, whereas in Europe it’s a 70% to 80% discount, said Dr. Wu.

Why? “Because manufacturing biosimilars is so costly, they will likely never achieve the savings of generics,” said Dr. Yamauchi. According to Gillian Woollett, PhD, senior vice president at Avalere Health, a generic drug costs about $1 to $5 million to move through the FDA approval process. A biosimilar, however, costs between $100–$500 million — which is in part the reason they won’t be discounted like generics. Dr. Yamauchi estimates that savings from biosimilars will not exceed 30% of the branded drug price.

Additionally, advances in disease treatment continue, and as a result the biosimilars of older generation treatments have to compete with newer biologic treatments. There’s a new generation of biologics that should be approved within the next year or two with promising safety and efficacy profiles, said Dr. Wu, noting risankizumab, a new drug that specifically targets IL-23 that will be approved in 2019.

WHAT’S IN A NAME?

Even if biosimilars were on the market as significantly cheaper alternatives to biologics, there is still confusion about the FDA’s biologics naming system.

In November 2017, the FDA adopted a new naming system for biologic products, including biosimilars, in which they added a random four-letter suffix to the end of biologics’ nonproprietary names. Previously, the suffixes were added only to the biosimilars’ nonproprietary names. This decision was not popular among many health care groups who wanted the FDA to attach meaningful suffixes for biosimilar names as was done for the first biosimilar approved in the U.S., filgrastim-sndz, whose suffix represents the manufacturer Sandoz.

“How can anyone remember these names? Obviously we can’t,” said Dr. Wu, who also preferred the suffix to represent the product manufacturer. He’s not alone. An ASBM survey of 400 physicians across multiple specialties showed that only 9% of physicians preferred a random suffix.

LABEL CLARIFICATION

For physicians confused about biosimilar labels, the FDA recently released its final guidance on labeling biosimilar products indicating that it will treat biosimilars like generics in that the label will appear nearly identical to that of its reference product. Of note is the inclusion of a “Biosimilarity Statement,” which describes the biosimilar product’s relationship to its reference product.

Additionally, the biosimilar label can now indicate certain deviations from the reference product label — for example, that only some presentations are available and only a subset of indications is offered. Because a biosimilar may not be licensed for all indications of a reference product, the FDA guidance specifies that the biosimilar label should include only the information relevant to the approved indications.

The clinical trial information included in the label should come only from the reference product, not the comparative data used to establish biosimilarity. The FDA has taken this approach to avoid potential misinterpretation of the comparative data.

“Basically, the package information for the biosimilar will be composed of the same information that is found in the reference product with regard to safety, efficacy, warnings, etc., and have no mention of clinical trial outcomes and any differences in pharmacokinetic, pharmacodynamics, or immunogenicity assays,” said Dr. Yamauchi.

The FDA did not provide guidance on the labeling of interchangeable products, but stated it plans to provide future guidance on this topic.

A BIOSIMILAR SUCCESS STORY?

In July 2018, the FDA released its “Biosimilars Action Plan,” an 11-step proposal that encourages competition in the pharmaceutical industry by streamlining the biosimilar approval process. While the first obstacle — FDA approval — doesn’t quite get a check mark, it’s on its way. “In order for biosimilars to be successful, there needs to be a salesforce to educate health care providers about the availability and cost-saving potential,” said Dr. Yamauchi. “There needs to be easy access without step therapy or prior authorization requirements.”

In many ways, biosimilars must compete in the marketplace as if they are a branded drug. They need physicians and patients to know about them and understand their safety and efficacy. Cost savings will only be recognized if physicians prescribe the drug, said Dr. Yamauchi. He believes time may solve this problem as more data is accumulated in pharmacovigilance programs, easing physician reluctance and uncertainty about biosimilars.

“Dermatologists need to learn more about biosimilars to feel comfortable prescribing them; however, most aren’t even available to prescribe so they don’t feel like they need to learn about them yet,” said Dr. Wu.

The irony is that the U.S. is by far the most efficient market in the world for generics, said Dr. Woollett. She believes biosimilars can be made more efficiently, but the question remains as to how they can be incentivized so that the cheaper product gets the market share and can prosper. “The FDA can do its part to make it easier and cheaper to get more biosimilars available, but whether that’s enough, none of us know yet — but it’s a start.”

Interchangeability

An interchangeable product is a biosimilar that meets additional data requirements outlined by the FDA. To be approved as interchangeable, the biosimilar must show that the product is expected to produce the same clinical result as the reference product in any given patient, and the risk in terms of safety or efficacy of switching between biological products must be no higher than using the reference product alone. Currently, there are no biosimilars designated as interchangeable by the FDA.

The FDA recommends performing three switch studies, in which you move back and forth between the reference product and biosimilar to ensure maintenance of safety, efficacy, and have no increased risk of immunogenicity, said Dr. Yamauchi.

Achieving an interchangeable designation is difficult and costly. “The amount of data the FDA requires to receive that designation is considerable. And so the question becomes is it so considerable that nobody could earn it because it’s unaffordable to ask the patient to pay more for an interchangeable product because additional studies have been done? It’s a difficult balance,” Woollett said.

Is interchangeable better?

Interchangeability is a legal designation. “There’s misinformation out there that an interchangeable biologic is a better biosimilar, and it’s not. It’s the same product on which additional studies have been done to earn that designation,” said Dr. Woollett.

A biosimilar that hasn’t been designated as interchangeable is like a Scottish verdict, said Dr. Woollett, in which a person can be deemed guilty, not guilty (innocent beyond a reasonable doubt), or unproven (an acquittal, but not enough evidence to prove innocence). Because a biosimilar has not been designated interchangeable does not mean that it could not be safely switched with the reference product. It simply means that the additional studies required by the FDA have not been performed, she said.

Interchangeability is significant primarily because it’s the only way a pharmacist could dispense a biosimilar in place of the reference biologic without consulting the prescribing physician (see “Physician notification” sidebar). “I am comfortable prescribing biosimilars, but what I’m not comfortable with is having the pharmacy switch them without my knowledge,” said Dr. Wu. While the issue of pharmacy substitution and physician notification is an important one to address legislatively, many biologics are administered in the physician’s office and not available through a pharmacy, which may reduce its impact.

What is keeping biosimilars out of reach and when will they be available?