Despite immense challenges and hurdles, biosimilars may be where generic medicines were in the mid-1980s.

With the new Trump Administration placing an emphasis on bringing healthcare and pharmaceutical costs down, it would appear that the door for more rapid development, entry, and expansion of biosimilar drugs in the United States might be about to swing open a bit wider.

But the reality is that several hurdles stand in the way, including two big ones: a slow-moving regulatory environment and intense legal resistance from drug innovators intent on protecting their hard-earned patents.

On the regulatory side, market professionals say that the U.S. got off to a slow start in biosimilar introduction and today lags behind Europe.

EMA 22, FDA 4

By the start of 2017, some 22 biosimilars already were approved by the European Medicines Agency (EMA), another 16 are pending, and the outlook through the end of this year is for possible “significant expansion,” according to experts at the law firm of Patterson Belknap Webb & Tyler LLP in a blog that appeared recently on the website Lexology.

In comparison, the U.S. FDA had okayed only four out of 16 through Q1 of this year.

“Our biosimilar pathway has taken some time to be created,” said David Picard, VP of Biosimilars and Injectables at AmerisourceBergen (ABC). While Europe has been involved in biosimilars for about 10 years, the U.S. approved its first biosimilar just two years ago.

Maneuvering Past Bumps in the Road

While it remains unclear to what extent Washington may be successful in driving a reduction in pharmaceutical and medical costs, the pressure might give a boost to the dozens of biosimilar projects that currently are in clinical studies.

But a lot also will depend upon the federal regulators and how quickly they can move past bumps that develop in the road.

For example, FDA’s recent issuance of guidance calling for what some may consider to be a rather unconventional naming convention for biosimilars.

Letter ‘Devoid of Meaning’

The guidance calls for a nonproprietary name assigned for each originator biological product, any related products, and the biosimilar product—one that should include a distinguishing suffix composed of letters that are “devoid of meaning.”

A variety of industry and healthcare professionals have voiced displeasure over the naming convention guidance contending that the suffixes instead should be meaningful and memorable to avoid confusion, perhaps even labeling a product as interchangeable.

But, it remains unclear whether the FDA would reconsider the naming convention method considering the reaction from the field.

In the meantime, the action potentially adds significant downstream cost.

“Think about the manufacturer, everything from the package insert to the box, the carton, the case, all the promotional material will have to reflect this new name,” Picard said, adding that every entity touching the product, including the distributor, hospital, and retailer, will have to change their systems to incorporate the new name.

Beyond the domestic “naming” issue, there also are international challenges faced since not every country refers to a biosimilar as a biosimilar.

In an American College of Toxicology webinar last August, Dr. Michael Leach, a therapeutic area lead for drug safety R&D at Pfizer, noted in his abstract, “Global terms used for biosimilars are … somewhat similar, but not highly similar.”

For example, “biosimilar” in the U.S., Australia, and China was also termed “similar biological medicinal product” in the U.K., “similar biotherapeutical product” by the WHO, and “biocomparable” in Mexico.

Meanwhile, the industry still awaits final guidance on biosimilar interchangeability, which originally had been scheduled for completion last year, but was extended by the FDA. The agency did, however, issue draft guidance on the subject in January.

Legal Concerns and Access to Innovator Samples

The next big hurdles that biosimilars are facing today are costly legal challenges, according to ABC’s Picard.

“The innovators are aggressively defending their biologic assets (IP and patents),” he said. “There are a couple of biosimilars that have received FDA approval, but are not going to see the market for some time because of that legal hurdle. But, certainly, the U.S. market is probably the largest consumer of these biologics so I’m not surprised that if you own that asset you’re going to do all you can to protect it from a legal standpoint.”

Getting beyond the regulatory, naming, and legal hurdles, another challenge biosimilar manufacturers face involves access to originator samples for comparability studies. It’s a costly process and the manufacturer will pay full list price, but they still need to get access.

“I wouldn’t characterize (the originators) as readily sharing,” Picard said, adding that there have been stonewalling instances triggered under the Risk Evaluation Mitigation Strategies (REMS) program.

“An unintended consequence of that program is that the innovators are able to say, ‘Sorry, I know you are looking for samples but it would violate my REMS program so I can’t give them to you,’” he said. “It’s probably not in every case but we’ve been made known of instances where that is happening.”

A couple of acts under consideration in Congress may help alleviate some of those challenges. One initiative is called the FAST Act and the other is called CREATES. Both are intended to provide easier access to innovator samples for comparison studies, but it remains unclear where Congress stands on the issue and whether positive rulings are likely.

The Complexity Hurdle

Another challenge for biosimilar manufacturers is the potential barrier to entry created by the sheer complexity of the undertaking, which is exponentially more challenging than, for example, backward engineering a chemical-based small molecule drug because the makers are dealing with live cells.

“The goalposts sometimes change over time, because the innovators introduce these process changes through the life of a biologic and sometimes the goal posts or parameters that a biosimilar is seeking to match change as well,” Picard explained. “I even heard anecdotally a comment from an innovator admitting that their own product has batch-to-batch variability and questioning how could a biosimilar filer possibly replicate that process given that their own product moves and changes over time.”

A Quick and Safe Path to Market Is Critical

Despite the regulatory, legal, and research complexities of manufacturing the costly biosimilars, the targets that are represented by the biologics are often measured in billions of dollars of annual sales, an attractive goal even at this very early stage of the pharmaceutical segment.

“Yes, it takes perhaps $100 million to file and develop these biosimilars as opposed to $2 million or $3 million for a small molecule drug, but if it’s a $10 billion brand you don’t need too big of a piece of that pie to get your investment back and gain some revenues and margins,” Picard said. “I think that’s what’s attracting people—the size of the prize if you will.”

ABC, a wholesale distributor to pharmacies, hospitals, and other healthcare-oriented facilities, touches about one third of all the biologics in the market today based on the company’s size and footprint.

With an even bigger footprint in the area of oncology products, Picard said the company has become very adept at managing the distribution of biologic products over the years and he anticipates that the distribution model for a biosimilar will closely resemble the biologic path.

“In fact, we’re suggesting to the biosimilar filers that they should likely follow the path that the biologic is in today unless there could be some efficiencies to be had by going a different path,” he said.

The manufacturers are generally receptive to that suggestion, he said, but it’s a bit across the board. “These folks are trying to get into the market in a cost-effective way so if they can get there by one method versus another that’s going to save them money, they’re interested in exploring that.”

How Long Before Biosimilars Grow Up?

Because the market for biosimilars still is relatively new, especially here in the U.S., it’s difficult to predict just when it will make significant inroads into generic and innovator turf.

Some estimates suggest that that point may surface in about five years as second and third biosimilars of the same molecule appear—something that may propel adoption rates and into a scenario that looks a little bit more generic-like.  

As Picard put it, “There’s a lot of wait and see at this point because it’s new—a little like generics were during introduction back in 1984—with some saying ‘let me watch and see, and let someone else take the risk. If things look okay, I’ll jump in.’”

This feature story can also be found in the April/May 2017 issue of Pharmaceutical Processing. 

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