An emerging class of biological products intended to act as the generic equivalents of earlier, branded products is being threatened globally by an obvious, yet complex set of issues, say two experts consulted by Regulatory Focus.
The products-known as biosimilars, follow-on biologics or subsequent entry biologics-are intended to act as interchangeable substitutes for other biological products whose patents have expired and are thus eligible for market competition. While the interchangeability between a biosimilar and its reference product is simple enough in theory-just re-create the patented product's protein structure and have regulators approve it-several problems make that process difficult.
One of the most basic problems is that no two biological products can be exactly alike. Because of the processes used to create biological products, proteins have subtle differences that are exacerbated when different manufacturing and processing techniques are used.
Global Regulators Take Varied Approaches
It will be up to regulators to determine-likely on a product-by-product basis-just how similar a biological product must to be to obtain approval, according to Kathy Wekselman, director of regulatory and scientific affairs for CTI Clinical Trial and Consulting Services, and leader of the Biosimilars Update session at the upcoming 2012 RAPS: The Regulatory Convergence.
"The big elephant in the room is interchangeability, and whether we're going to consider a biologic product more like a New Molecular Entity (NME)-a new product that has a similar function but is a completely different drug in how we prescribe it-or if we going to be able to see biosimilars as interchangeable."
Though some regulators, including the European Medicines Agency (EMA), have already approved numerous biosimilar products, most have deferred to regional regulators on the issue of interchangeability.
Health Canada has, meanwhile, put its foot down on the issue, saying that biosimilar products are not interchangeable and dubbing them 'subsequent-entry biologics (SEB),'" she added. "They've come down very strongly on the side of, 'no, these are different, and they're not interchangeable and they can't be.'" Canadian provinces could still pay for SEBs, however.
FDA, Other Regulators Approach Interchangeability Issues Slowly
Officials with the US Food and Drug Administration (FDA) remain vague on the issue, per Wekselman.
Under the 2010 Biosimilar Price Competition and Innovation (BCPI) Act-passed with the Patient Protection and Affordable Care Act (PPACA)-FDA is required to release a definition for interchangeable products. Thus far, however, the agency has only released limited information on the principles of interchangeability.
"They've said that it's possible, but the drug company would have to show that nothing happens to the patient if you switch them back and forth between the two products. But how the company would show that to regulators remains wide open," said Wekselman.
Those principles were outlined in three draft guidance documents released in February 2012. A fourth draft guidance document, Submission of Clinical Pharmacology Data as Evidence of Biosimilarity for Biologics and Protein Products, is due out by the end of 2012, according to FDA.
"Theoretically [interchangeability] is supposed to be able to happen, but how it's going to happen and the specifics are pretty far in the future at this point," concluded Wekselman. "It's very treacherous territory for the regulatory agencies," she added, as they will be under enormous pressure to balance demands from legislators, branded industry, the generics industry, patient groups and safety advocates.
This will require regulators to carefully calibrate and release draft guidance and regulations, which has historically been a slow process.
"The top trend among global regulators right now is getting more guidance out there about specific classes of biological drugs," said Wekselman. "For instance, how you demonstrate biosimilarity for different kinds of products, such as biotechnology-derived proteins and alpha- and beta-interferon products.
"We're only just getting into the stage of specific guidances for specific biologic products."
Legal Issues Likely to Become Interwoven With Interchangeability
Just showing that products are interchangeable with one another is likely to be a challenge, according to George Yu, an attorney with the law firm of Schiff Hardin LLP who specializes in intellectual property, and will present at the Strategic Development of Biosimilars workshop at 2012 RAPS. Companies want to protect their diverse intellectual property, including patents, which represent a significant investment above and beyond the development of their drug.
The exact production processes used to manufacture the drug, for example, might prove to be stumbling blocks for biosimilar manufacturers. "It's not as if FDA is going to tell the biosimilar company what the branded side company is doing, but this information acts as a source of comparison between the two products," including proving interchangeability, Yu said.
Interchangeability issues could also be a major component of litigation. Yu noted, "This might be a source of challenge by the branded side companies later on, that the biosimilar product is not, in the literal sense, biosimilar."
Branded product companies could also change their reference products on a continual basis to try to keep ahead of their competitors by forcing their products to remain biosimilar to the reference listed drug (RLD), something commonly done with generic pharmaceuticals. "You might, as a generic company, be testing against a target that has moved a little bit," Yu explained.
"Any issue that can be litigated, will be litigated"
The good news for companies trying to understand the legal uncertainties of developing and marketing biosimilar products is that much of the existing case law regarding generic pharmaceutical products is likely apply to biosimilars.
The bad news for everyone who isn't a patent lawyer: the number of patents likely to be litigated could explode, along with the cost of the trial. Yu notes that the "typical" biotechnology litigation case focuses on just a handful of patents. "The issue here is going to be managing a litigation that could have tens of patents involved, if not over one hundred." Yu explained he was unaware of any other area of patent law in which so many patents could be involved in just a single case.
Most of the patents are for uses of a particular drug. A drug such as Humira (adalimumab), an anti-tumor necrosis factor (TNF) inhibitor, can have dozens of patents on its various treatment properties, any one of which can lead to a lawsuit.
Surviving a legal process to show interchangeability, then, could be a financial burden on all but the largest companies, according to Yu, who noted he had heard estimates of projected legal costs in excess of $100 million for some products. "I personally think that's a bit high, but for your typical patent litigation involving between one and five patents, you could easily expect to budget more than $2.5 million. While there might be some marginal savings involved in litigating a larger number of patents," litigating dozens of patents will still be costly.
He added, "There are some pretty strong reasons why someone might want to go through the regular Biologics License Application pathway," particularly in light of those costs. "Because of the stakes involved, any issue that can be litigated, will be litigated."
What's in a name? Branded and Generic Product Companies Square Off
Even if a biosimilar is able to demonstrate interchangeability to FDA, that is unlikely to be the end of its troubles. Some companies have already filed Citizens Petitions with FDA arguing that any biosimilar product should be forced to use a different, branded name as opposed to a generic one. Generic names could also be affected, said Yu. "What they're suggesting is that if a company wanted to develop a biosimilar product, they would have to call it something other than the generic name."
The concern comes down to pharmacovigilance practices and the ability to accurately pinpoint a problem product. Though generic pharmaceutical products went through a similar battle with branded innovators, they ultimately came out on top. This will not necessarily be the case. "The argument is that biological products are so complicated and even products that have reportedly the same active ingredient may have different immunogenicity profiles or other characteristics such as half-life and circulation because of the way the biosimilar was made. The concern that is expressed by some branded-side companies and patient groups is that the branded product should remain distinguishable," said Yu.
Different countries have approached this issue differently, according to Wekselman and Yu. Health Canada has demanded that countries use different names, as it does not recognize their interchangeability. EMA, meanwhile, has put out guidance documents for generic-named products.
Other countries, such as Japan, have gotten around this by adding a prominent suffix to the end of the generic name to indicate that it is a biosimilar product-an approach that could eventually be replicated elsewhere, such as in the US, which has not yet taken a stance on the issue.
Many of these issues will only be solved in time, Yu stated, "Because everything is new here, there's still a lot for everyone to learn about the process. It will be interesting to see what happens. Nothing is going to substitute for the actual experience in working with these products."
Both Kathy Wekselman and George Yu are speaking about biosimilar products at 2012 RAPS: The Regulatory Convergence, in Seattle, WA. For more information about the conference and the biosimilar track, please see the 2012 RAPS web page.