Part 2: Axinn Patent Attorneys Discuss New Challenges for Insulins Under the BPCIA

The Center for Biosimilars^® (CfB): Hello, I'm Matthew Gavidia. Today on MJH Life Sciences^TM Medical World News, The Center for Biosimilars^® is pleased to welcome back Ted Mathias, a partner with Axinn, Veltrop and Harkrider LLP, and Stacie Ropka, also a partner with Axinn, Veltrop and Harkrider LLP.

Stacie, is the Purple Book currently designed and provided by FDA analogous to the Orange Book?

Ropka: So, the BPCIA does not statutorily mandate the creation of an Orange Book analog. The creation of the Purple Book was actually initiated and then assembled by FDA. And the Purple Book does have some good information for follow-on biologic developers, such as the licensing date so that the 12-year exclusivity period, which will be discussed in more detail later on, can be calculated. But what is missing, perhaps the most desirable part, is the list of patents that may need to be addressed before the launch [of a biosimilar]. This is not surprising, again, because FDA does not compile the patent list for the Orange Book. Only the reference product sponsor is truly in a position to identify patents that might be part of patent litigation or some other type of patent dispute resolution.

Now, while there is no patent list in the Purple Book, there is the patent dance where the reference product sponsors and follow-on biologic developers together identify the patents that will be addressed in litigation that will most often take place prior to the launch of a follow-on biologic. Step 3A of the patent dance requires the reference product sponsor to provide a list of patents to the follow-on developer that they think can reasonably be asserted against the follow-on developer in patent litigation.

But this list is provided after the follow-on developer has already made the business decision to pursue a specific biologic and provided the follow-on application to FDA and to the reference product sponsor. In other words, they've already spent quite a bit of money. So, a patent for the reference product sponsor is not available to aid [biosimilar developers] in making the earlier business decisions as it is in the Orange Book.

In addition, since the patent dance mandates that the 351(k) applicant timely provides a document similar to a notice letter, and they have a statutorily mandated 60 days after receiving the 3A list, the extra time to develop arguments that an early patent holder would provide is unavailable under the current version of the BPCIA.

Now, recognizing that the BPCIA does not include provisions mandating an Orange Book analog, a number of bills were drafted last year to address the issue. Unfortunately, that legislation was stalled. Regardless, some of the provisions in the various bills might provide insight into what format the statutorily mandated Purple Book might take. Specifically, the various bills provide provisions regarding how a patent list will be developed. One bill suggests that during the patent dance, that 3A lists should be submitted to FDA and then FDA would include them in the Purple Book.

But some criticisms have already been in regard to that method for developing a patent list because the 3A list is supposed to be tailored to the 351(k) application at hand, and that may be either underinclusive or overinclusive for some other 351(k) applicants. And thus, it will not solve issues regarding the number of patents that must be addressed before one can make business decisions regarding whether or not to pursue a follow-on biologic.

Also, if the 3A list is used for the patent list, the first follow-on developer will not have the benefit of that list because the list isn't developed until the patent dance has already started for at least 1 follow-on developer. So, that person will not have access to that list and thus, will not be able to make the business decisions regarding whether or not to develop their follow-on.

In addition, because the BPCIA allows asserting any patent instead of the average 1 to 25 patents that we typically see for a Hatch-Waxman litigation, BPCIA litigation can technically involve over 100 patents. So, there are also proposed bills that are going to try to limit the number of patents that can be asserted in litigation. It's not completely clear if those bills would also limit the number of patents that can be listed in the Purple Book.

As currently drafted, the provisions in these various bills regarding patent litigation under the BPCIA, and a mandated Purple Book are not entirely satisfactory to either side. When Congress turns their attention back to these bills, I would expect much debate and input from all stakeholders. One aspect that seems clear, though, is because patents that qualify for litigation during the patent dance include any patent that referenced sponsors believe can reasonably be asserted, a Purple Book patent list would likely have in addition to the method of use and to the actual product itself, the manufacturing patents and the patents that are directed to medical devices that are used for administration, such as injection pens and the like.

CfB: Ted, what trends do you foresee in litigation involving follow-on insulins?

Mathias: We're seeing that reference sponsors are focusing on building their portfolios with patents on injectors and other delivery systems. One possible reason for that is that a lot of these insulins have been around for quite some time. As patents on insulins, insulin formulations, methods of using insulin and processes of making insulin all expire, reference sponsors are focusing on patents directed to systems of delivering the insulin. So, whereas before there is litigation involving drug patents on one hand and litigation involving medical device patents on the other, the lines are really blurring. We're expecting to see litigations that really combine the 2 disciplines.

CfB: And Ted, additionally, how will this trend then affect follow-on drug developers?

Mathias: Developers with expertise in drug substances, for example, solid oral dosage forms, will need to develop a comfort level with medical devices. There are development challenges, IP challenges and regulatory challenges. Drug companies can seek R&D [research and development] help from outside sources and develop in-house resources in order to develop their capabilities with respect to medical devices. Particularly when they are partnering with third parties, trade secret issues are likely to be much more prominent than they've been in the past.

And then, for in-house counsel, as far as the IP challenges, they might be very familiar with drug patents but far less familiar with medical device patents. So, that provides an additional learning curve for in-house counsel.

And finally, FDA is likely to have additional approval requirements for different kinds of medical devices. This could become particularly significant if a follow-on developer attempts to design around a reference sponsor’s device patents.

CfB: Speaking about our last main topic, which is the impact on uptake, Ted, how might the 12-year exclusivity under the BPCIA impact the rate of biosimilar entries under the insulin category?

Mathias: For follow-on insulin developers, there's good news and there's bad news. The good news is that FDA has said reference insulin products that were approved under Hatch-Waxman, meaning prior to March 23, 2020, are not entitled to any portion of the BPCIA’s 12-year exclusivity term. And FDA also says that those same reference products are not entitled to any exclusivity that they might have had left over from under Hatch-Waxman. So, unless FDA's interpretation of the statute is rejected by a court, there are some insulins that follow-on developers could actually bring to market earlier because of the switch to the BPCIA. So, that's the good news.

The bad news is the long-term outlook. And for reference insulins that get approved under the BPCIA, they're going to have 12-years of exclusivity, rather than the minimum 3 years to the maximum 7 years they were entitled to under Hatch-Waxman. So, once we start to see reference insulin products approved under the BPCIA, it's going to be a long time before we see any follow-on versions hit the market.

CfB: Stacy, will consumer acceptance of insulins approved under 351(k) and BPCIA be stronger or less so than previously under 505(b)(2)?

Ropka: That's an interesting question. There were only 2 follow-on insulin products that were approved under the 505(b)(2) pathway before March 23, 2020. Although the 505(b)(2) pathway is abbreviated, the insulin product approved was considered a new drug. From all accounts, the new drug was able to readily gain market share and become profitable for the developer. But now that follow-on insulin pharmaceutical products are subject to the approval process set out in the BPCIA, they will be approved as either a biosimilar or an interchangeable version of the reference product.

Now, so far, FDA has only approved biosimilar versions of reference products and we know uptake of those biosimilars has been slow in the United States. One explanation is that early on, end users, such as physicians and patients, were somewhat suspicious of the safety and efficacy of biosimilar products. Because the 351(k) pathway provides for 2 designations, either the biosimilar or the interchangeable, it was thought that a biosimilar designation was not as good as an interchangeable designation with respect to safety and efficacy. In fact, there are articles indicating that physicians and patients should wait for interchangeable follow-on biologics and forego biosimilars all together.

Now, to some extent, this attitude still exists. While some physicians are now more comfortable starting new patients on the biosimilar product, there's a little more hesitancy when considering changing a patient from a reference product to a biosimilar version of that product.

Another reason for the slower uptake of currently approved biosimilar products today is that many biologic pharmaceuticals are administered by third parties, either in hospitals, doctor's offices or infusion centers. And the decision to supply the biosimilar versions of reference biologic pharmaceuticals depends more on the internal pharmacy list, that is the formulary, and to some extent less on the physician and the patient.

For at least this reason, it has been suggested that the interchangeable designation may not be as important for these third party administered biologics. Of course, if a follow-on biologic is not even included in the formulary, there's no chance that the patient will receive it, and that will be problematic for developing a follow-on market.

But drugs like insulin, which are purchased and self-administered by the patient, the patient needs to know and be willing to ask for a biosimilar version of a reference product and the physician was specifically prescribed that biosimilar version. Thus, a biosimilar version of an insulin product may experience slow uptake by patients, either because they're just uninformed or they do not want to take a biosimilar.

CfB: And building off that, Stacie, how might this spur drug developers to pursue interchangeability designations?

Ropka: If a follow-on insulin biologic can be approved as an interchangeable, it would qualify for automatic substitution at the pharmacy, at least in those states that currently allow for such automatic substitutions. In that case, I would expect uptake to be more robust. With an opportunity to have an easier path to market share, I would expect 351(k) applicants for insulin products to seriously consider the interchangeable route.

In fact, in the joint development between Mylan and Biocon, they indicated that they will seek an interchangeable designation for their insulin glargine product, Semglee. Semglee, which is a follow-on to reference product to Lantus was actually approved under the 505(b)(2) pathway after March 23. There is hope that the analytical and clinical program supporting approval will be sufficient to support the interchangeable designation.

CfB: And speaking of which, Stacie, has FDA provided any guidance to address what is required to obtain an interchangeability designation for insulin products?

Ropka: Yes. In November of 2019, FDA provided a guidance regarding clinical immunogenicity entitled "Considerations for Biosimilar and Interchangeable Insulin Products." As Ted mentioned, typically, the interchangeable designation requires these switching studies in order to determine if a biosimilar product that is intended to be given more than once will result in the production of other antibodies by the patient. That is a clinical immunogenicity such that the biologic product is rendered unsafe, ineffective or both.

In the November 2019 guidance regarding requirements for obtaining interchangeable designation for insulin, FDA has indicated that the comprehensive and robust comparative analytical assessment between a proposed interchangeable insulin product and the reference product that can demonstrate that the interchangeable product is highly similar to the reference product and has a very low residual uncertainty about immunogenicity might be approvable as an interchangeable without the switching studies.

FDA has actually indicated that it would expect to have little or no residual uncertainty regarding immunogenicity of insulin products, because the current analytical tools that are used to evaluate quality attributes for insulin products can support such a comprehensive analytical comparison, enough to support a conclusion that a particular proposed biosimilar insulin product that is highly similar to its reference product generally wouldn't have little or no residual uncertainty regarding immunogenicity and would be expected like the reference product to have minimal or no risk of clinical impact from immunogenicity.

CfB: Lastly, are there any concluding thoughts either of you may have?

Mathias: I'll go first. One issue to keep an eye on as interchangeable products gain regulatory momentum is the potential impact of state laws on automatic substitution. There's an argument that the BPCIA's automatic substitution provision preempts state law, but it doesn’t. Automatic substitution of interchangeable products at the pharmacy will be subject to a patchwork of state laws that impose varying requirements for automatic substitution. And these state laws represent another potential obstacle to uptake of follow-on biologics, and it's one that could become much more important this decade than it's been over the last 10 years.

Ropka: And I would like to add to that. Once we have clarity regarding automatic substitution at the pharmacy, I would expect a robust, interchangeable market to form providing reduced costs to patients but still being profitable for developers, which would encourage the continued development of interchangeable products and result in more competition and again, lower prices. And these lower cost insulin options are important to our health care system because the prevalence and incidence of diabetes represents a large percent of the US population. Around 10% of the population has diabetes and many of them are going to require insulin at some point to manage their condition.

CfB: To learn more, visit our website at centerforbiosimilars.com, I'm Matthew Gavidia. Thanks for joining us.