What Happens When Switching Among Biosimilars?

Late last year, I wrote about a biosimilar challenge that could be on the horizon. With the approval of the second infliximab biosimilar (infliximab-abda by Samsung Bioepis), that horizon is a lot closer. However, we are no closer to understanding how to address the issue.

When Renflexis™ is launched in October (it is unknown whether the US Supreme Court ruling that wiped away the 180-day postapproval waiting period will affect this), 3 noninterchangeable versions of infliximab will be available. Based on patient turnover in health plans, the following scenario will soon occur.

 

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Image Copyright 2017 by Lee Fogel

Mr. Jones, a 39-year-old man with Crohn’s disease, works for a large self-funded employer. He has been taking Remicade®, the reference product, for some time. In January 2018, his employer decides to change its plan offerings. His new health plan does not cover Remicade, favoring Inflectra® (infliximab-dyyb) instead. He could seek a medical exception to continue on Remicade, but his new plan actually offers considerable incentives to switch, including significantly lower cost sharing. After discussing the situation with his doctor, he makes the change, and experiences much the same clinical results. In 2019, his employer makes another change in plan. And this plan covers Renflexis on the specialty tier but has Remicade available on the higher-cost nonpreferred specialty tier. He and his physician are unsure of the best move.

Keep in mind that it would be rare and probably makes little sense for a health plan to cover both biosimilars and the reference product. At some point, the plan will seek a contract that leverages marketshare. In the scenario above, at what point does the patient unduly risk the development of neutralizing or antidrug antibodies?

No data have been published on switches among 3 biosimilar products. These agents are not designated as interchangeable—though Pfizer’s Inflectra may be closest to it based on its NOR-SWITCH investigations; therefore, no one is truly confident of what might or might not occur with regard to efficacy or safety. I suspect it may be some time before switches among reference product, biosimilar A, biosimilar B, or even biosimilar C may be considered routine.

Patients receiving biologic products for serious chronic diseases may also be subject to case/care management. This is not a clean transition when changing health plans. The situation described above will likely happen in the near future with infliximab and possibly adalimumab (once the patent litigation is cleared). It would be a good idea for health plans and insurers to start reviewing their options now to ensure both patient safety and cost-effective decision making.

US Supreme Court Strikes Down 180-Day Waiting Period

In a unanimous decision, the Supreme Court rejected Amgen’s oral arguments—a biosimilar manufacturer can meet the 180-day notification period requirement by notifying the originator’s manufacturer before receiving approval. In other words, biosimilar launches can occur immediately after approval by the Food and Drug Administration (FDA).

The 180-day notification period was seen as giving the originator a further 6 months of exclusivity, not allowing newly approved products to reach the market until after the period had expired. The argument by biosimilar manufacturers has been that notification of its intention to commercialize the drug can be given prior to approval (e.g., at the time the application is sent to the FDA), without any disadvantage in terms of an examination of whether patents had been infringed.

Sandoz v. Amgen involved Sandoz’s filgrastim biosimilar Zarxio®, which has since launched, but this decision, written by Justice Clarence Thomas, will clear one barrier out of the way to faster access to biosimilars.Image result for justice clarence thomas

The justices decided to punt on a ruling of whether the patent dance is necessary to the states, where unfair business conduct laws may take precedence. The patent dance involves a protocol where the biosimilar applicant must provide to the reference drug maker information on how it plans to manufacture the agent and its actual 351(k) application. The reference drug manufacturer can then evaluate which of its patents it believes will be infringed, and must respond (and counter) within a specific timetable. According to Justice Thomas’ opinion, “There is no dispute about how the federal scheme actually works, supreme-courtand thus nothing for us to decide as a matter of federal law. The mandatory or conditional nature of the [Biologics Price Competition and Innovation Act] requirements matters only for purposes of California’s unfair competition law, which penalizes ‘unlawful’ conduct. Whether Sandoz’s conduct was ‘unlawful’ under the unfair competition law is a state-law question, and the court below erred in attempting to answer that question by referring to the BPCIA alone.

“We decline to resolve this particular dispute definitively because it does not present a question of federal law. The BPCIA, standing alone, does not require a court to decide whether §262(l)(2)(A) is mandatory or conditional; the court need only determine whether the applicant supplied the sponsor with the information required under §262(l)(2)(A).”

Justice Stephen Breyer suggested, in a concurring opinion, that the FDA may play a greater role in deciding the outcome of the patent dance. He stated, “[If FDA], after greater experience administering this statute, determines that a different interpretation would better serve the statute’s objectives, it may well have authority to depart from, or to modify, today’s interpretation.”

No Clear Winner on Supreme Court’s Biosimilar Hearing Day

Despite the fact that the arguments at Wednesday’s Supreme Court wrestling match on the patent dance and 180-day notification issue went into overtime, there was no clear winner discernable in Amgen v. Sandoz.

Some observers believe that the Supreme Court justices were more comfortable with Amgen’s arguments, but the justices admitted that there was little clarity in trying to interpret the ambiguous language of the Biologics Price Competition and Innovation Act. Justice Stephen Breyer stated his unfamiliarity with the technical aspects of the field and expressed concern about ruling on these issues.

Indeed, it is possible that the Court will not issue any ruling, since the case specifically arose around Sandoz’s launch of Zarxio®. Sandoz waited out the 180-day notification period before launching the product, which could prompt the justices to decide that the question is moot, avoiding the larger question of whether it should be enforced for future biosimilar launches.

Judicial experts and industry watchers will be pouring over the comments and questions from the justices for some time, until a final ruling is released (thought to be in July).

In other news… US sales of Janssen’s Remicade® slipped 2.4% to $1.18 billion, in the first full quarter following the launch of its biosimilar competitor, Pfizer’s Inflectra®. This does not necessarily reflect lost marketshare but Janssen’s concessions in matching the price of Inflectra to retain its preferred positioning. With a new competitor looming later this year (Renflexis™), Remicade’s earnings slide is expected to accelerate.

Amgen’s Enbrel® is also facing a less-rosy future, as the product’s sales in the anti-TNF category has begun to slip, independent of any active biosimilar competition. However, competition in the rheumatoid arthritis and psoriasis categories from other products, especially interleukin inhibitors, has been stiff. First quarter 2017 sales of Enbrel in the US dropped 15% to $1.18 billion. Sandoz’s biosimilar etanercept, though approved by the FDA and beyond the 180-day notification period, has not yet launched due to patent litigation questions.

An Eventful Week for Biosimilars

It has been an eventful week in the biosimilar world during a rather uneventful beginning to 2017. The next likely FDA decision on a biosimilar will not occur until reviews of Samsung Bioepis and Merck’s version of infliximab or Coherus Bioscience’s version of pegfilgrastim are completed sometime in the second quarter.

However, the biosimilar world is girding for the opening arguments April 26 in the Supreme Court’s hearings on the validity of the 180-day notification (exclusivity) period. To this end, the Biosimilar Council issued a lengthy amicus brief arguing cogently that Congress did not intend to provide 12.5 years of marketing exclusivity to biologic manufacturers. Several others have petitioned the court with similar arguments, including AARP and America’s Health Insurance Plan. In fact, I would be interested in reading an amicus brief in defense of the notification period.

The Biosimilar Council’s parent organization recognized an opportunity was opening wide, and decided to rename itself. The Generic Pharmaceutical Association is now officially the Association for Accessible Medicines.

The European Medicines Agency handed Celltrion the approval for the first biosimilar of an anticancer monoclonal antibody. Truxima™ is a biosimilar version of rituximab, which will compete against MabThera® (which is also marketed as Rituxan® in the US). Celltrion has partnered with Teva to market the biosimilar in the US, if and when the FDA approves the agent. Celltrion is yet to file for FDA approval. Two other monoclonal antibodies have been filed with the FDA for the direct treatment of cancer—trastuzumab (Mylan/Biocon) and bevacizumab (Amgen/Allergan), both of which are expected to yield FDA decisions in the latter half of 2017.

Finally, a study was published this week that highlighted the overall cost problem for the health care system—the price of cancer medications are persuading significant proportions of cancer survivors to skip their drugs or specifically request lower-cost alternatives. It is well known that cancer diagnoses are one of the most common reasons for medical bankruptcy. An earlier literature review of the financial implications of cancer reported that more than half of cancer survivors were in debt as a result of their cancer treatment, and roughly half of cancer survivors experienced some form of financial distress. These investigators stated that depending on the study, between 4% and 45% of these patients “did not adhere to recommended prescription medication because of cost.”

Supreme Court to Hear Sandoz v. Amgen Arguments on the 180-Day Notification Period

It seems that the Supreme Court will in fact hear Novartis’ case in an attempt to overturn the 180-day notification period, as part of the “patent dance.” Its biosimilar-making subsidiary (Sandoz) will finally get its day in the nation’s top court in April, with a decision expected sometime in July.

The announcement has taken many by surprise because of an announcement by the court in December that it would not hear a similar case involving Apotex v. Amgen.

Although any new decision by the Supreme Court will have no bearing on the circumstances of the original case—Sandoz launched in September 2015 after sitting out the 180-day notification period—it will have important ramifications for biosimilars coming to market in the future. It is widely viewed that this notification is wholly unnecessary. This mandate of the BPCIA was intended to allow the completion of patent litigation, but instead is seen as an extension of the originator product’s exclusivity period.

However, even if the Supreme Court rules to strike down this unintended additional period of exclusivity, it may have relatively little effect in getting biosimilar products to the market sooner. Instead, the remaining patent litigation will prevent most drug makers from a quick launch after receiving Food and Drug Administration approval.

Supreme Court May Hear Biosimilar 180-Day Notice Suit

How soon after approval by the Food and Drug Administration (FDA) can a biosimilar be sold on the market? For a conventional generic drug, that is pretty much completely up to the manufacturer. For a biosimilar maker, they have to sit and wait.

The US Supreme Court has asked the Obama Administration for its views on the contentious 180-day notice period, mandated by law, that biosimilar manufacturers must give to makers of innovator products, indicating their intention to go to market.

The Biologics Price Competition and Innovation Act (BPCIA), which authorized the biosimilar approval pathway, also set the timing of when a biosimilar can be launched. Specifically, BPCIA stated that a biosimilar manufacturer must give 180-day notice to the innovator’s manufacturer before the agent can be launched. The original notion was that this 6-month period would allow for the resolution of any patent dispute brought by the innovator drug maker. This seems unnecessary in reality, as patent disputes have been initiated and underway for many months/years before FDA approval is given. Instead, the 6-month notice period is undully delaying product launch (and depriving the government and the public of cost savings), according to Sandoz, which petitioned in February for the US Supreme Court to decide the matter.

In 2015, Sandoz contended that the law allowed it to give Amgen notice of its marketing plans for Zarxio® before FDA approval was granted. The federal appeals court did not agree, forcing Sandoz to wait essentially another 6 months before going to market.

According to industry observer Ed Silverman, this means 2 things: (1) that it is likelier that the Supreme Court will hear the case and (2) that the Obama Administration, which had lobbied for shorter exclusivity periods than was actually granted in BPCIA (7 yr vs. 12 yr), may have another chance to influence how quickly biosimilars are brought to the marketplace.

Sandoz argues that it should be allowed to provide this notice well before FDA approval, as patents are being disputed well before hand; Amgen counters that notice of intention to launch is moot without FDA approval. Of course, with an 8-member Supreme Court, a tie would allow the appeals court decision to stand.