 was decided by the Supreme Court. What have we learned since then about the Biologics Price Competition and Innovation Act (BPCIA)?

, there were significant concerns that many biosimilar applicants would provide 180-day notice of marketing the day an aBLA, or an Abbreviated Biologics Licence Application, was filed, and that an immediate [declaratory judgment, DJ] action would be filed right after that, so you’d just aboid the BPCIA patent dance and thus completely flout Congressional intent. 

But here we are about a year later, and fears of chaos have not yet been realized. According to the data we have collected for BiologicsHQ, only 2 biosimilar manufacturers have so far refused to participate in the patent dance, and one of them still provided their aBLA. Only twice has a biosimilar manufacturer, in the middle of the patent dance, given the 180-day notice of commercial marketing and subsequently filed a DJ action that same day without completing the patent dance. And, in both of those cases, the DJ action was ultimately dismissed. 

Really, what we’ve seen is that for the most part, at least with respect to the biologics cases that have been filed since 

, companies are choosing to at least start the BPCIA patent dance proceeding, and generally have followed through with most of it. Usually when it hasn’t been completed it was at the negotiation stage when the parties are trying to determine the number of patents to litigate in the first round of the litigation.

We also haven’t seen a lot of issues with federal law not giving the ability to compel production of an aBLA, as there has only been once instance where the biosimilar manufacturer has refused to give the innovator access to their aBLA.

We also have seen that companies generally aren’t launching at-risk. Out of the 11 biosimilars that have been approved so far*, only 3 have launched at-risk.

So, the bottom line is that there hasn’t been as much of an impact as we expected, but that certainly doesn’t mean things won’t change in the future.

Videos

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, discusses lessons learned about the Biologics Price Competition and Innovation Act in the year following Sandoz v Amgen.

Ha Kung Wong: The BPCIA 1 Year After Sandoz v Amgen

Were there elements of the Trump administration’s blueprint on reducing drug prices that caught your eye?

So this document, entitled “American Patients First” and which was released in May of 2018, has a lot of different aspects to it. Although this idea wasn’t specifically delineated in the May 2018 blueprint, which isn’t surprising seeing the lack of detail in that release, the Trump Administration has recently included the idea of importing drugs from other countries as part of meeting some of its stated goals. This is particularly interesting in the context of biosimilars.

My understanding is, pursuant to this plan, that the FDA will form a working group to explore importation in cases where a manufacturer suddenly increases the price of a drug that doesn’t have any competitors. It’s also my understanding that importation would only be allowed for drugs whose patents and exclusivities have already expired.

As an initial matter, this means that this importation is unlikely to impact access of more cutting-edge medications, which significantly limit its impact on drug prices. So it’s unclear whether this plan would significantly address any of the stated goals.

But more specific to biologics, as a practical matter, it may be difficult to determine whether all the patents have expired given there is no current listing of patents covering biologics products like there is in the Orange Book for small-molecule drugs. So it may be difficult to determine whether you apply for this or not.

There are also concerns about how we will determine whether these imported drugs are as safe as those approved by the FDA. This is especially concerning in the biologics context where no 2 drugs are exactly identical in the way that a small-molecule drug can be.

As an example, even if you’re using the exact same process and the exact same machinery, producing a biologic in Seattle will be different from producing one in Phoenix, will be different from Miami, and so on and so on. Based on differences in environmental conditions, ambient temperature, all that—it can completely change the product that you’re going to get.

And then there’s also just normal product drift even in the same manufacturing location with biologics. That’s because most biologics are manufactured from living cells, which may have significant variance from cell culture to cell culture even without considering the surrounding environment. It seems allowing importation of biologic drug products into the United States, without further FDA oversight, could create a loophole for avoiding the costly biosimilar approval process in the United States, which may ultimately also create potential safety concerns.

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, discusses the Trump administration's proposal to allow importation of drugs, including biologics.

Ha Kung Wong: The Importation of Biologics and Biosimilars 

In the Biosimilar Action Plan, the FDA suggested that it may work more closely with the Federal Trade Commission (FTC) on addressing anticompetitive behavior. What might that look like in the biosimilars space?

Similar to what we’ve seen in the small molecule drug context, the FDA and FTC are likely to try to address practices by innovators that may delay competition.

As an example, this may include potential misuse/abuse of Risk Evaluation and Mitigation Strategies (otherwise known as “REMS”), such as making it difficult for biosimilar manufacturers to obtain samples of innovator products for [research and development, R&D] purposes or denying access to shared REMS systems.

REMS was created to make sure that the benefits outweigh the risks of using any particular drug product, including ensuring safe conditions for administration of drug products. Since biologics, and thus biosimilars, frequently require injections or unique administration procedures with sensitive components requiring precise storage or precise application, REMS might be used to require additional safeguards, such physician confirmation and presence, before certain biosimilars are administered, which may ultimately limit access.

This could potentially be done without impacting the [Biologics License Application, BLA] product, as biosimilars are not considered exact copies, nor are they considered to be substitutable, unless they are an interchangeable.

Of course, proper application of REMS is incredibly important, but the indication that the FDA will work closer with the FTC for biosimilars might mean much greater scrutiny of REMS in the future.

Additionally, we are likely to see more scrutiny of settlement agreements that may impact biosimilar competition. Although the frequency of district court litigations and [inter partes review proceedings, IPRs] pertaining to biologics are in flux, it’s possible we see more and more potential settlements so as to achieve more certainty for various manufacturers, meaning a higher potential for FTC intervention.

So far, we have seen 1 antitrust lawsuit related to biosimilars brought by Pfizer against Johnson & Johnson. We could also see the FTC bringing antitrust suits against biologic drug manufacturers or insurers that it deems to have anticompetitive practices that are blocking biosimilar market entry.

So there may be a lot more oversight for biologics practices in the future from the FTC.

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, discusses how the FDA and Federal Trade Commission (FTC) might work together to address anticompetitive behavior in the biosimilars marketplace. 

Ha Kung Wong: FDA and FTC Cooperation to Address Anticompetitive Behavior 

As a litigator, one of the things that particularly caught my attention was the FDA’s commitment to enhancing the Purple Book to make it more useful. Currently, unlike the Orange Book for small-molecule drugs, the Purple Book doesn’t list any of the patents that cover the biologic products. This has created a challenge for biosimilar manufacturers, as they have to attempt to determine the entire scope of patents protecting any drugs they are developing essentially through their own internal analysis.

With the Orange Book and small-molecule drugs, FDA guidance pursuant to 21 C.F.R. § 314.53(b)(1) is clear that applicants may list “drug substance (or active ingredient) patents, drug product (or formulation and composition) patents, and method-of-use patents.” Applicants, however, may not list process patents, patents claiming packaging, patents claiming metabolites, and patents claiming intermediates.

It’s unclear from the limited information that the FDA has given whether they will able to include similar patent information in the enhanced Purple Book, but if that were to be included, it could change litigation strategies going forward.

For example, more patents may see IPR (or inter partes review) challenges as the biosimilar manufacturer wouldn’t need to wait to go through the [Biologics Price Competition and Innovation Act, BPCIA] patent dance procedure to identify all of the patents relevant to a biosimilar drug and could start bringing the challenges earlier.

It may also decrease the incentive to use the BPCIA patent dance as the patents that could be involved would already be identified. From an innovator’s perspective, identifying all the patents that could be infringed by biosimilar manufacturers could be difficult without knowing the manufacturing methods they are using. And perhaps more importantly, if innovators are unable to list process patents in the Purple Book, similar to what’s in place for the Orange Book, there could be a significant loss of efficiency on both sides, as process patents tend to be much more important and unique for biologics than they are for small molecules.

From the perspective of an innovator, anything the FDA does to speed up the approval process will make litigation that much more important for protecting their products from biosimilar competition once any regulatory exclusivities have ended. Earlier approvals could cause us to see more biosimilar manufacturers attempting at-risk launches and cause us to see more related legal procedures such as requests for temporary restraining orders and preliminary injunctions.

The FDA said that it will be creating updated guidance for biosimilar manufacturers that are seeking approval for fewer conditions than the reference product is approved for. More guidance informing this practice could change both innovator and biosimilar manufacturers’ assessments of the strength of patent portfolios, as method of treatment patents may become less valuable in protecting biologic drugs from competition.

The FDA also noted that they will be working together with other government partners to take corrective action if they see evidence of practices that create an imbalance between innovation and competition that is contrary to statutory intent. This may mean we will see extra scrutiny of litigation and IPR settlements that are interpreted to potentially delay biosimilars from reaching the market.

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, discusses key features of the Biosimilar Action Plan.

Ha Kung Wong: The FDA's Biosimilar Action Plan

How are your patients responding to the idea of switching to a biosimilar from a reference biologic?

So, I think a person who’s barely controlled…I wouldn’t switch them, because I don’t know what’s going to happen. A person who is incredibly well controlled, I suspect there will be no problem. A person who’s on methotrexate and well controlled, where I suspect methotrexate is doing half the work, again, I don’t have any concern.

But, there are people who can’t use methotrexate, who are sort of hovering at the low disease activity mark and sometimes flare, but mostly they’re doing quite well. I wouldn’t switch those people, I wouldn’t touch them. So, I think that everyone needs to have some consensus about where it’s okay, where it’s possible, and where you just don’t change anything.

I think that, at this point, I know the insurance companies and the pharmacy benefit managers believe they are making good decisions for our patients, but they need to include the patient’s rheumatologist in the decision.

Vivian Bykerk, MD, associate attending rheumatologist at the Hospital for Special Surgery, associate professor of medicine at Weill Cornell Medical College, discusses switching patients to biosimilars. 

Vivian Bykerk, MD: Switching Patients to Biosimilars

Are you comfortable with using a biosimilar for your patient? 

I’m comfortable in starting my patient on a biosimilar versus its originator, assuming that it works equally well, that there are no glitches in access, and that the federal government has inspected the makers of that biosimilar as much as they inspect the originators, because I know there is a whole process of compliance and specifications that needs to happen.

I worry that they’re able to do that if they’re made in India or Korea or wherever. I’m not so worried about the biosimilars that are made in this country by the companies that are already making them in this country, because we know there are differences, so I would want to see very careful inspection of the company or manufacturing plants that are making them.

So, let’s assume all of that is the case and the process of accessing the biosimilar is equal to the process of accessing the originator, so you don’t end up with short falls—the needle works as well, the boxes are similar, all of the practical considerations&mdash;I think it would be fine.

What I do not want to see is people being forced off of their drug that works, or multiple switching. Even worse, I don’t want to see multiple switching where I’m not told or the patient is not told. For that matter, I don’t want to see [any] switches [at all] where I’m not told or the patient isn’t told.

Vivian Bykerk, MD, associate attending rheumatologist at the Hospital for Special Surgery, associate professor of medicine at Weill Cornell Medical College, describes her level of comfort with using biosimilars in practice. 

Vivian Bykerk, MD: Using Biosimilars in Treating Patients

Why is it important for patients with RA to get treatment early in the course of their disease? 

You can imagine, if you allow each joint to be infiltrated with a large number of immune cells that are creating messengers, we call them cytokines, and other messengers that seek to destroy, basically cause damage, that you don’t ever want those joints to get to that stage.

In other words, we want to meet people when they’re first developing achiness and maybe the first swollen joint, so that we can literally control that and limit—modify the disease, in essence&mdash;the development of proliferative synovial tissue in the joint that causes damage.

Once that horse is out of the barn, it’s really hard to manage it. It’s possible, but it usually requires a whole level up, in terms of therapy.  

Vivian Bykerk, MD, associate attending rheumatologist at the Hospital for Special Surgery, associate professor of medicine at Weill Cornell Medical College, explains why treating rheumatoid arthritis (RA) early is crucial. 

Vivian Bykerk, MD: Treating RA Early

What’s the burden of out-of-pocket costs for patients who rely on biologic drugs? 

I think from the patient perspective…there’s a big surprise for patients. I think we’ve seen a significant rise of high-deductible health plans, and a lot of people with chronic diseases purchasing those high-deductible health plans, in part, because the premiums associated with those high-deductible health plans are significantly lower. Patients have begun to rely on needing that high deductible with their copay assistance programs.

So, I think what we’re most afraid of, most recently with out-of-pocket costs regarding these specialty drugs, is that patients have come to rely on a way of getting by the high-deductible health plan that may be going away, and they may not be aware of that.

In our advocacy efforts, one of the things we’re working on is to educate patients that they really have to look into their health plan, especially their high-deductible health plans, and understand if copay accumulators are being applied to that policy.      

Stephen Marmaras, director of policy and advocacy for the Global Healthy Living Foundation, discusses the burden of high-cost biologics.

Stephen Marmaras: The Burden of High-Cost Biologics

How would you like to see prior authorizations change to reduce the burdens for patients and physicians? 

When we talk to physicians that treat patients with many of the chronic, complex diseases that make up our community, they tell us that it’s maddening the diversity of prior authorization forms. Unfortunately, many of them tell us it’s only the offices that devote full-time staff to prior authorization forms where you see patients getting the drugs that their physicians prescribed.

We think that that’s just an absolutely ridiculous system where patients are only receiving the drugs their doctors prescribed because there’s staff on hand to process forms. So, what we’d like to see done is have more legislation pass that requires uniformity of prior authorization forms. Florida took a massive step forward in doing that last year, but I think there’s still more reform efforts that need to be undertaken.

I think we need to apply some penalties to that type of legislation, so that if insurers are found to not be in compliance with standardization of prior authorization forms that there’s some sort of monetary penalty for doing that, per instance, not for a totality. It’s really critical that insurers are talking to physicians. I think that physicians need to be engaged really on a focus-group level in state—specifically in-state, talking with the specialists in-state or even general practitioners to some degree&mdash;to get an understanding of what are the major hurdles and barriers in the prior authorization forms that currently exist.

I think that a lot of times there are no answers to those questions and those conversations haven’t been had. They need to occur. We’d love to help them occur, we’d love to connect insurers in states with specialty physicians that we know have had difficulty, and their patients have had difficulty, with processing prior authorization forms.

But we should never live in a world where a person with a chronic disease can’t get access to a drug because their doctor or staff hasn’t or can’t fill out a form correctly or doesn’t have the time to fill out a form because it’s so onerous.

Stephen Marmaras, director of policy and advocacy for the Global Healthy Living Foundation, discusses the challenge of prior authorizations.

Stephen Marmaras: Prior Authorizations for Biologic Drugs

Do you see cost playing a role in patient access to biologics?  

Cost and access to biologics is an issue, but it’s maybe not an issue that the patient sees themselves because there are always ways to cover some of the copays. So yes, there’s a small cost, and there is a cost to using biologics. The payers have figured out how to fund them, and they figured out formulas that work for them on how to fund what, so each insurance company might fund different ones. In a way, access for patients to any given biologic is dictated by their particular insurance company. The cost is either being taken out by insurance companies, or it’s taken out by government, and that is becoming a challenge for payers, and I’m calling them all payers because they are costly. I think it’s important to note that the cost that’s advertised as the so-called, “real price,” is not what the payers are paying. So, it’s a little bit misleading to say that they are as expensive as they are because there’s no way that’s what people are paying for them.  

Vivian Bykerk, MD, associate attending rheumatologist at the Hospital for Special Surgery, associate professor of medicine at Weill Cornell Medical College, discusses how cost affects patient access to biologic therapies.

Interviews