Comparing Biosimilar Approval Progress by the FDA and EMA

It is widely reported that European biosimilar development is way ahead of that in the US. In a number of ways, this is true. However, when talking about biosimilar development in the EU compared with the US, we really should take a look at the bigger picture.

First of all, let me specify that I’m talking about biosimilar approvals, not launches. In the latter case, the US is way behind, not even viewable in the distance.

Obviously, the US lags because it got a later start, first in promulgating the BPCIA in 2010, and then in developing the biosimilar regulatory pathway. The US system then tried to shoot itself in the foot with the “patent dance,” which also does not exist in the EU. Even America’s inability to master the steps of the patent dance did not deter initial interest in biosimilars, from inside and outside the nation. Overall, the US failed to take great advantage of the pioneering work of European policy makers in divining a regulatory pathway for biosimilars, and has been playing catch up ever since. In a sense, however, the US’s regulatory machinery has caught up, and perhaps exceeded the pace of the European Medicines Agency (EMA) in approving biosimilars.

Biosimilar approvals

This is a complicated comparison, outside of numbers alone. The chart below offers a view to the Food and Drug Administration’s (FDA’s) 17 current approvals, all accomplished within seven years of the pathway being available (and the seventh year, 2019, is still young). An analysis of information from the Generics and Biosimilars Initiative demonstrates that only 13 biosimilars were approved in the EU seven years after the pathway was implemented.

A closer look reveals a couple of important points: (1) The EU’s first biosimilar approvals were for growth hormone drugs, which were not considered biosimilar products in the US (until 2020); (2) epoetin biosimilars dominated 2007 approvals with five; and (3) filgrastim biosimilars comprised the main approvals for 2008–2010 in the EU. Between 2009 and 2012, the EMA approved only three biosimilars, two of which were filgrastim molecules. In 2013, an impressive array of biosimilars were approved in the EU, including yet another filgrastim and growth hormone, two infliximabs, and follitropin. The EU has made tremendous progress with new molecules over the past couple of years, including the rush of rituximabs in 2017, and pegfilgrastims and adalimumabs in 2018, all corresponding closely with patent expirations. In fact, of the 54 biosimilars approved in the EU (as of December 2018) in its 13 years of experience with biosimilars, 30 (55%) were approved in 2017 or 2018.

That doesn’t mean the FDA hasn’t made missteps—there have been plenty. Remember, the patent dance was not FDA’s doing, that was statutory not regulatory. They do need to admit their responsibility on the four-digit suffixes and the long delay in finalizing guidances, especially on interchangeability. And there are certainly biosimilar drugs that were approved by the EMA but rejected by the FDA.

Overall though, the FDA has not been the reason only seven biosimilars in four drug classes are now available for prescription. Those are uniquely American problems.

Tidal Wave of Pegfilgrastim Biosimilars About to Hit Europe

We had mentioned the upcoming deluge of adalimumab biosimilars aiming to hit the European market in mid-October, but another biosimilar tidal wave may actually precede this.

The European Medicines Agency (EMA) has had an extremely busy week in the pegfilgrastim biosimilars arena. In addition to granting marketing authorization to Coherus Biosciences for its pegfilgrastim biosimilar, it has also approved the marketing of Pelgraz®, a pegfilgrastim produced by Accord Healthcare. In addition, the EMA’s Committee for Medicinal Products for Human Use has also recommended approval for three pegfilgrastim biosimilars—from Sandoz, Cinfa, and Mylan.

Mylan is the only drug maker with a marketed biosimilar version of pegfilgrastim in the United States. Its product Fulphila® hit the US market in early July. Coherus’ product, Udenyca™, is awaiting a November 2 decision from the Food and Drug Administration. Coherus is reportedly looking for a partner to market its pegfilgrastim biosimilar overseas, while it intends to market the product internally in the US. This means that Accord may have the first pegfilgrastim biosimilar to reach patients in the EU, though this advantage will be short lived should Mylan in particular gain approval.

In other biosimilar news…Boehringer Ingelheim announced positive results in its clinical study of Cylteza® versus Humira® in patients with moderate-to-severe plaque psoriasis. The study results were announced at the European Society of Dermatology and Venereology.

Samsung Bioepis Co., Ltd. announced that the FDA has accepted its 351(k) application for SB5, a biosimilar to adalimumab. Samsung is the fourth manufacturer seeking to enter the biosimilar market for Humira. Two have been approved (Amjevita® by Amgen and Cyltezo® by Boehringer Ingelheim) but are not yet marketed. A decision on Sandoz’s application is expected later this year.

Amgen/Allergan Score Positive EMA Evaluation, but Launch Will Be Delayed

A couple of noteworthy pieces of news have emerged from across the pond on the biosimilar front. The first involves progress for Amgen’s application for its bevacizumab biosimilar at the European Medicines Agency (EMA). Its drug evaluation arm, the Committee for Medicinal Products for Human Use, recommended approval of the biosimilar on November 9.

Assuming EMA final approval is received, however, Amgen and Allergan’s cancer treatment agent will not be marketed any time soon. The principal European patent is not set to expire until 2022.

Image result for avastin biosimilarIn the US, Mvasi™ was approved by the Food and Drug Administration in September, but its launch is similarly delayed by patent litigation. The main US patents should expire in 2019 (Roche claims to hold 27 enforceable patents). Amgen had filed suit October 6 challenging the validity of the patents in question, but this case may not be heard until late 2018. Amgen has the option of launching “at-risk,” but it has not indicated that it will go this route. Otherwise, the earliest launch may be sometime in 2019.

Several other potential bevacizumab makers have already challenged the patents, according to other reports. These include Boehringer Ingelheim, CelltrionPfizer, and Samsung Bioepis.

In other related news…An announcement will be made on November 20 regarding where the EMA will relocate its headquarters as a result of the Brexit. The Agency will need to complete its move by March 31, 2019, when Britain’s divorce from the European Union is finalized.

Sandoz’s Pegfilgrastim Biosimilar Under New Review at EMA

On October 27, Sandoz announced that the European Medicines Agency has accepted its re-application for review of its biosimilar version of Neulasta® as supportive treatment in patients receiving cytotoxic chemotherapy.

PrintSandoz’s attempt to bring its biosimilar pegfilgrastim to the market was stalled in the US in Q2 2016, when the FDA issued a complete response letter. It had withdrawn its application to the European Medicines Agency in January 2017. However, the new application seems to be bolstered by additional data, according to reports.

Sandoz is expecting to reapply to the FDA in 2019, according to its website.

As noted too often in this space, the journey to approval for a pegfilgrastim biosimilar has been marked by failure and setbacks. However, as shown in the Figure from the MarketRealist, revenues for Neulasta are considerably larger than that for its nonpegylated progenitor, Neulasta (filgrastim). This is a powerful impetus for potential biosimilar manufacturers to succeed. At close to $5 billion in annual revenues, there is little reason to think that a biosimilar pegfilgrastim will not be approved eventually.

Market Realist.png

Source: The Market Realist.

In other news… AbbVie expects its Humira sales to jump to $21 billion by 2020 from $16 billion today, evidently bolstered by its successful defense of its patents against Amgen.

Mylan and Biocon Withdraw Two EMA Biosimilar Applications

The biosimilar pegfilgrastim marketplace may have taken another hit today, as Biocon announced that it was pulling its applications for both pegfilgrastim and trastuzumab from consideration by the European Medicines Agency (EMA).

The action came after Biocon was notified of the need for re-inspection of its manufacturing site by the European authorities. According to Reuters, Biocon said in a stock filing, “The European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products,” Biocon said, without specifying when the regulator would carry out the inspection.

Herceptin“We are on track to complete our corrective action and preventive actions by the end of this quarter, and it is our intent to seek re-inspection and re-submission thereafter.”

In another report, a Biocon spokesperson stated that “Whilst our drug substance facilities for trastuzumab and pegfilgrastim were approved, the European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products. The request for withdrawal of the dossiers and re-submission is part of the EMA procedural requirements linked to this re-inspection and will be considered by the EMA’s Committee for Medicinal Products for Human Use (CHMP),” said the company spokesperson.

This action could potentially create considerable problems for the partners Mylan and Biocon. They have the opportunity to be first-to-market in the US with regard to both biosimilar products. Their biosimilar trastuzumab application received a unanimous recommendation to approve from the Food and Drug Administration (FDA) Oncology Drug Advisory Committtee in July, and a final decision is imminent (expected before September 3). The partners’ biosimilar pegfilgrastim application is expected by October 9th. Although the FDA usually rules according to its Advisory Committee recommendations, manufacturing plant problems has resulted in at least one surprising rejection, for Pfizer’s Retacrit®. Pegfilgrastim applications have not yet made it through the FDA approval process, after three previous attempts.   

Information is not readily available as to whether the Biocon plant that is subject to re-inspection would potentially be supplying products to the US. If so, the FDA may decide to review the situation, and possibly delay their decision or issue complete response letters on the two products.

Restating the Record on Biosimilar Safety and Efficacy

At this point in time, it may be a bit more difficult to find professionals who are convinced that approved biosimilars are not as safe and effective as the originator agents. The call of those manufacturers defending their long-time marketshare is being drowned out by (1) informational sites published by major pharmaceutical manufacturers and marketers, and (2) the facts presented by the governmental agency with the most experience approving and regulating biosimilars—the European Medicines Agency (EMA).

Several manufacturers have excellent resource sites on how biosimilars are manufactured and how they differ from the originator products. These include “minor” players such as Amgen, Merck, Pfizer, among others. Their sites are pretty informative, and do not seem to be developed strictly as a marketing platform for their biosimilar products. As a group of resources, they are contributing to a public educational effort to ease potential concerns with biosimilars.

The immunogenicity and extrapolation issues are historically the greatest points of sensitivity to patients and providers. The EMA issued a report in May 2017 that summarized its findings over 10 years of biosimilar surveillance—there is no evidence of safety problems or efficacy problems with approved biosimilar products since the first licensed product. “Extrapolation is not a new concept but a well-established scientific principle used routinely when biological medicines with several approved indications undergo major changes to their manufacturing process (e.g. to introduce a new formulation). In most of these cases, clinical trials are not repeated for all indications and changes are approved based on quality and in vitro comparability studies,” states the report. Moreover, “Over the last 10 years, the EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicines.”

Although this is absolutely true for the first-generation of biosimilars, the monoclonal antibody biosimilars have been licensed by the EMA more recently, with the first being infliximab in 2013 and the last being rituximab and etanercept in June 2017. Over time, utilization and evidence will accumulate to support their safety and effectiveness in real-world practice and across multiple indications. Yet, the potential for immunogenicity, which several switching studies have shown is low, will eventually fade as a concern.

The “Eprex Incident” of 1998 remains the sole alarm bell for a true product safety problem related to the manufacture of a biosimilar-type of product (predating by several years the introduction of biosimilars and biosimilar approval regulations, even in Europe).

Obviously, the past does not predict the future. That is one reason why organized surveillance efforts are needed both in the EU and in the US to capture any safety signals. However, it does seem that products making it through the regulatory approval systems are delivering the promised results.