Tag: biosimilar

Frustration Mounts as Sandoz’s Etanercept Biosimilar Launch Delayed into 2018

Call it irritation, exasperation, or frustration, but biosimilar manufacturers and payers alike are feeling it, as the fight over drug patents has barred the way to approval for yet another biosimilar for a costly biologic.

In this case, Sandoz’s Erelzi™, which was approved by the Food and Drug Administration on August 30, 2016, has been caught in the patent litigation web. The originator drug, Amgen’s Enbrel® was first approved in 1998. Amgen asserts that its patent on the agent protects exclusivity until 2029, which would give Amgen 31 years of sole marketing rights. Despite the unlikely event that it can defend its patent for this extraordinary period, Sandoz has acknowledged that it will need to hold off launch of the biosimilar until at least 2018.

In a report from Reuters on January 25, Richard Francis, CEO of Sandoz, stated that the legal battle “won’t really reach a conclusion until 2018. That’s the frustration sometimes of the legal situation, but the way I look at that, we’re carving the landscape out as we go.”

Indeed, Sandoz has been at launch-delaythe forefront of legal battles, also fighting Amgen on the validity of the 180-day notification period, which is now being readied for US Supreme Court arguments in the Spring. The 180-day notification period for Erelzi was due to end in
late February 2017. After this time, Sandoz may still launch the product, at risk of financial penalties and loss of revenues, if the courts rule that Amgen’s remaining patent is valid.

However, the potential for savings on Enbrel, through biosimilar competition, continues to be a mirage for payers. The agent, which pulled in US revenues of $5 billion in 2015, has been the subject of numerous recent price increases. Health plans and insurers, while believing these costs untenable, may have little choice but to pay up or find ways to more aggressively restrict access.

Second European Medical Society Endorses Biosimilar Use

A large European medical association has followed on the heels of the European Crohn’s and Colitis Organization, in outlining its support for the use of biosimilars. This time, the European Society of Medical Oncology (ESMO) has endorsed biosimilars for the direct treatment of cancer, seemingly in time for upcoming European approvals. esmo-logoposition paper, ESMO acknowledges that a large number of patents will expire for several monoclonal antibodies by 2020, and that in Europe, price reductions could be as high as 40%.

In a press release from ESMO, President Fortunato Ciardiello stated, “Biosimilars are must-have weaponry in financially sustaining healthcare systems on a global scale as well as significantly improving outcomes for an increasing number of patients throughout Europe and the rest of the world.” He added, “Biosimilars give us the chance to make treatment options for cancer more affordable everywhere.”fortunato-ciardiello-md-phd

Although the European Medicines Agency (EMA) does not have a mechanism for approving the interchangeability of biosimilars with the originator drugs, this decision on drug switching is left to the EU member states. In its position paper, ESMO advises member states to “consider the precautionary principle as well as the potential risks associated with substituting a reference biological medicinal product with a biosimilar when tendering for hospitals. Nine out of 28 Member States completely prohibit automatic substitution of biosimilars for reference products by pharmacists. Six out of 28 Member States restrict substitution to ensure the safety of patients and in particular, avoid unforeseen immune responses. There is no clear consensus among Member States concerning this issue, implying that countries may decide whether to implement policies related to automatic substitution or not.”

However, ESMO advises that automatic substitution should be avoided, and switching allowed only if “(1) the physician is well-informed about the products; (2) the patient is fully briefed by the physician and (3) a nurse is closely monitoring the changes and tracking any adverse events.”

The EMA is currently considering the approval of biosimilar rituximab for its oncology indications in addition to rheumatoid arthritis, and trastuzumab for the treatment of breast cancer.

Interchangeability Guidance Released, FDA to Require Switching Studies

On January 10, the Food and Drug Administration (FDA) released its long-awaited draft guidance on the interchangeability standard for biosimilar manufacturing.

It’s been quite a while since we have been able to discuss progress on interchangeability, so as a reminder, the practical differentiator between a product designated as biosimilar versus interchangeable is that the latter “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Not surprisingly, the critical mandated addition in clinical studies of an interchangeable biosimilar is the conduct of a sufficient number of switching studies; that is, studies where patients are alternatively given the originator product, switched to the biosimilar, and possibly back to the originator, without any measurable risk to patient safety or efficacy. Or as the FDA puts it “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Interestingly, the FDA does restrict switching studies to between the biosimilar and the US-licensed reference product only (i.e., no EU versions with bridging studies). The reason is related to slight, nonclinically meaningful differences that may be introduced in the EU version that is not present in the US originator product.

The draft guidance is subject to a 60-day public comment period. For those interested in commenting on the guidance, they can visit https://s3.amazonaws.com/public-inspection.federalregister.gov/2017-01042.pdf for instructions.

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.

Large European Society Lends Its Support to Switching

In a recent statement published in the Journal of Crohn’s and Colitis, the European Crohn’s and Colitis Organization (ECCO) announced its support for switching from an originator product to a biosimilar in patients with inflammatory bowel disease  (IBD).

In its position statement, ECCO asserts that switching from the originator to a biosimilar in patients with IBD is acceptable if it is in line with national recommendations and has been discussed among the physician, nurse, pharmacist, and patient. This view, which represents a change from ECCO’s previous position, is based on the clinical experience gained from investigational studies and postmarketing trials using the biosimilar version of infliximab.

Lead author and President Elect of ECCO, Silvio Danese, MD, said, “Findings from the 2015 ECCO survey of IBD specialists found that around 80% of specialists are either totally confident, very confident or confident enough in using biosimilars, which is a huge change compared to 39% when a similar survey was conducted back in 2013.”

As for all biologics, traceability should be based on a robust pharmacovigilance system. The authors also noted that several postmarketing studies are ongoing or near publication, which lends further support to the improved confidence in the safety and efficacy of the biosimilar (Celltrion’s Remsima®, which is marketed in the US as Inflectra®).

This marks a significant shift in attitude from the previous ECCO position paper, which advised that switching from an established biologic to a biosimilar was inappropriate and called for more data on the safety and benefit of biosimilars in general.

Dr. Danese and his colleagues concluded, “there have been no reports so far that switching from the reference to the biosimilar infliximab [Remsima] has caused problems, in either adult or pediatric IBD patients. On the contrary, an increasing number of publications have shown that there are no safety or efficacy concerns about switching.”

Celltrion’s Rituximab Recommended for Approval in Europe

Just weeks after Celltrion presented data at the American College of Rheumatology meeting demonstrating that its product CT-P10 is as safe and effective as Rituxan® for the treatment of rheumatoid arthritis (RA), the European Medicines Agency (EMA) received the recommendation to approve the product for use in the EU.

The Committee for Medicinal Products for Human Use sent its recommendation to EMA on December 15. Assuming the regulator grants marketing authorization, CT-P10 will be sold as Truxima™ and will be indicated for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, RA, granulomatosis with polyangiitis GPA, and microscopic polyangiitis.

The originator product in the EU is MabThera®, which was licensed in 1998. If approved, it will be the first CD20-inhibiting monoclonal antibody to reach the market in a biosimilar version.

In other news from Europe: EMA Launches Consulting Pilot for Biosimilar Manufacturers. In what may be a page taken the US Food and Drug Administration’s (FDA’s) playbook, the EMA is offering scientific advice, starting February 2017, for companies seeking to bring a biosimilar to market. As part of the FDA’s biosimilar development program, it meets with manufacturers at various stages to consult on their analytical and clinical testing projects. The EMA’s pilot initiative does seem to be more limited, however, in that it offers a presubmission consultation. The pilot is said to run for up to 6 requests for scientic advice.

Are 2 Biosimilars to the Same Originator Product Biosimilar to Each Other?

In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.

We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?

What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.

Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.