Part 1: Axinn Patent Attorneys Discuss Insulins Under the BPCIA vs Hatch-Waxman

The Center for Biosimilars^® (CfB): Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences 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. Can you both just introduce yourselves?

Mathias: Yes, I'm Ted Mathias. I'm a partner at Axinn, Veltrop and Harkrider LLP and I focus on patent litigation, primarily in the life sciences, pharmaceutical patent litigation, medical devices, and also biologics, of course.

Ropka: My name is Stacie Ropka. I'm also a partner at Axinn and in addition to being a lawyer, I'm a PhD in microbiology and immunology. Prior to becoming a lawyer, I was a bench scientist in immunology, virology and neurology for 21 years, and I was on the faculty at SUNY Upstate Medical University. My legal practice focuses on Hatch-Waxman litigation and litigation counseling in the biologics and the human cell and tissue product technology.

CfB: To start us off, the regulatory move from insulin as a drug to insulin as a biologic has generated great discussion. Ted, can you please explain the approval process for insulin products under the Hatch-Waxman Act versus the Biologics Price Competition and Innovation Act (BPCIA)?

Mathias: Yes, until March of this year follow-on insulin products were approved through pathways of spelled out in the Hatch-Waxman Act. Generic versions of insulins technically could be submitted for FDA approval with an abbreviated new drug application [aNDA]. I say technically because FDA made clear that an aNDA would need to show more than your bioequivalence that would be the normal case for a small molecule drug product. But FDA for insulin products never specified what exactly an aNDA sponsor would need to do to obtain approval.

So, the result is that no insulin product was ever approved pursuant to an aNDA. And instead what follow-on insulin makers did is they submitted 505(b)(2) applications, where they relied on some data from the reference product. And in addition, they submitted varying degrees of information about their own product depending on the product similarities and differences from the reference product. But in any event, those 505(b)(2) applicants provided more data than required of an aNDA sponsor.

Now, since March 23, that's all changed, and follow-on insulin products must now be approved as biologics under 1 of 2 pathways provided by the BPCIA. One option is to seek approval as a biosimilar which requires showing that the follow-on is highly similar to the reference biologic product in terms of both its structure and its function and has no clinically meaningful differences from that reference product.

The second option under the BPCIA is to seek approval as an interchangeable. Interchangeable products must demonstrate that they are highly similar, ie, a biosimilar. In addition to that, for biologic pharmaceutical products, that are tended to be given to patients more than once, the sponsors also have to show that the risk in terms of diminished safety and efficacy of alternating or switching between use of the follow-on product and the reference product is greater than the risk of using the reference product without such alternation or switch. So, that is any immune response by the patient the follow-on biologic cannot result in a change in safety or efficacy that's greater than repeated dosing of the reference biologic product.

FDA issued a draft guidance in May 2019 specifying that switching studies which compare the immune responses in patients when switching, for example, from a reference product to the proposed interchangeable product and then back to the reference product. However, these studies are quite time consuming and expensive.

CfB: Stacie, is approval under 351(k) going to be more difficult than before or less so?

Ropka: This is really a yes and no answer. Approval under the BPCIA, whether you're seeking the biosimilar designation or the interchangeable designation, requires a thorough understanding or a thorough characterization of the reference biologic product and thus you are submitting more data to the FDA for approval.

And this is because a 351(k) follow-on biologic product must be more akin to a copy of the reference biologic product versus getting approval under Hatch-Waxman 505(b)(2) pathway, which actually results in the approval of a new drug, albeit via a somewhat abbreviated pathway. So, it is typically more time consuming and, of course, more expensive to get approval and will follow-on under the BPCIA than getting approval of a follow on under Hatch-Waxman.

But is it more difficult to get approval under the BPCIA? Given that the BPCIA has been in effect for 10 years now, and I think we're up to 28 products that have been approved by FDA, FDA has been able to provide more clarity regarding the types of studies and data they need to review in order to make a decision on approval. In addition, the technology used for demonstrating biosimilarity has greatly improved over the past 10 years.

So, FDA has provided more clarity for the approval pathway and the technology has improved to allow implementation of that pathway so that today, it can be less difficult to get the data required by FDA for a robust 351(k) application. Under Hatch-Waxman, FDA never really articulated a pathway from the approval of a true generic insulin product using an aNDA and as Ted said, under Hatch-Waxman, no truly generic insulin products were approved. Only a couple were approved under that somewhat abbreviated 505(b)(2) pathway, which is also provided for under Hatch-Waxman.

So, in one sense, it will be easier to seek a follow-on insulin product under the BPCIA because the pathway to biosimilarity has been established and has been successfully followed by both follow-on developers and FDA. However, for the foreseeable future, it will be time consuming and expensive to obtain approval under the BPCIA.

CfB: Ted, how does the BPCIA incentivize an insulin developer to pursue approval for follow-on insulin products?

Mathias: Well, Stacie referred to the clarity that the BPCIA provides and that in itself incentivizes follow-on insulin developers. The interchangeable pathway provides a more tangible incentive. The first licensed interchangeable can qualify for an exclusivity period, which typically lasts a year. So, that's similar to the exclusivity period that the first filing generic of an aNDA application enjoyed under Hatch-Waxman. However, 505(b)(2) filers under the Hatch-Waxman Act did not receive any exclusivity period.

Another incentive that the BPCIA provides for interchangeable is it they're eligible to be automatically substituted at the pharmacy, which was not the case for 505(b)(2) follow-on products. So, the BPCIA does provide, on paper at least, meaningful incentives. But there's a catch, and the catch is that no biologic has yet been approved as an interchangeable. There are reasons to think that might change soon, but we certainly are not there yet.

CfB: Moving on to the impact this regulatory change will have on litigations. Stacie, can you explain the advantages of the Orange Book under Hatch-Waxman and whether these advantages are lacking under the new pathway?

Ropka: So, there's this publication and the official name is "The Approved Drug Products With Therapeutic Equivalence Evaluations," but it is more commonly known as the Orange Book and it provides information from FDA on what drugs have been approved by FDA based on safety and effectiveness. Those would be new drugs and those are the types of new drugs that are typically available as a reference product. There are dates of approval and what entities obtain that approval. There are also drugs listed that have been approved based on a therapeutic equivalence evaluation. Those would be the generic drugs that were approved based on an aNDA.

One thing in the orange book that is not provided by FDA is a list of patents that can be asserted against generic drug developers, those would be your aNDA filers or developers using that 505(b)(2) pathway. And these are patents that before those developers or filers launch their product, they may have to deal with those patents in litigation.

Now, FDA does not provide that list. Instead, the patents are submitted by the new drug developer as part of the new drug application and the submission of patents is mandated by statute. The statute also limits what types of patents are eligible to be listed in the Orange Book. No manufacturing patents are allowed to be listed in the Orange Book, and it's an open question regarding whether the listing of patents that covers strictly medical devices are allowed. But patents that cover the drug and methods of using the drug are required to be listed in the Orange Book. The Orange Book is relied on by drug developers from making business decisions to pursue generic or follow-on products. The patent list is particularly useful because it lets a generic drug applicant or in 505(b)(2) applicant know very early on what patents may have to be challenged or otherwise addressed before they can launch their generic or follow-on product. These developers can use the patent list to decide if they even want to pursue an abbreviated application for a reference product or if they'd rather wait till the Orange Book list of patents expire or near expiration.

But it is 2-edged. For developers using the Hatch-Waxman statute. Every patent in the Orange Book must be addressed with respect to infringement and invalidity it in what is known as a notice letter, which is then, provided to the new drug developer and patentees after the end up or 502b2 application has been filed before litigation commences. Some of these notices can be fairly lengthy. Having a patent list early on provides the applicant more time to prepare their noninfringement and invalidity arguments that will be included in that notice letter well in advance of the 20-day deadline that is mandated by statute.

There are no provisions in the BPCIA for this Orange Book counterpart. FDA decided to create a Purple Book, and in its current form, FDA provides much of the same information for approved biologic pharmaceuticals that they provided for new drugs in the Orange Book. But just as FDA is not responsible for identifying patent information to list in the Orange Book, they do not identify patent information for listing in the Purple Book.