Tag: biosimilars

Lessons for Biosimilars From the Generic Drug Industry

The utilization of generics in the US is vast, upwards of 86% of all prescriptions in 2017, according to the latest research by IQVIA. The pace of generic drug approvals by the Food and Drug Administration is also impressive, with 767 last year. This does not ensure the future of the generic drug industry, however, said Doug Long, MBA, IQVIA’s Vice President of Industry Relations. If we’re not careful, biosimilars in the pipeline could suffer a fate similar to that for newly approved generics.

Doug Long, IQVIA
Doug Long, IQVIA

In his yearly update presented at the Academy of Managed Care Pharmacy 2018 annual meeting on April 25, Mr. Long said that despite near-record numbers of generic approvals over a three-year period, “only 30% of these generics were actually launched. That’s not happened before.” The reason is that the manufacturers, upon receiving approval, reevaluate the marketplace prospects for their product and the competition. “They decide not to throw additional money into a losing proposition,” he stated. In fact, of the 767 generic approvals, only 73 were first-time generics. Ninety percent were simply piling competition onto already crowded drug categories.

He terms it a race to the bottom, but not a death spiral for generics. That is, “we’ve already reached the bottom, and we will come off of it” at some point. Generic drug manufacturers’ reticence to launch will help change the market direction.

Biosimilars have vast potential to save health care dollars, but only if they are launched. In a couple of instances, manufacturers have reviewed their biosimilar positions (Shire, EMD Serono) while early in the pipeline. Though it is reasonable to expect a paring back of prospective biosimilar drug makers, we hoped this would happen once the marketplace becomes saturated. That of course has not happened.

More Evidence of Value in Generics

Although several generic drugs have been associated with steep price increases, the net price change in 2017 for generics was -7.2%, according to Mr. Long. Most of this was the result of large rebates. Despite 86% generic drug prescribing, generics account for only 13% of the revenues. “I think there will be more generic drug shortages as a result of this revenue picture. People are refusing to launch after receiving approval, based on the dynamics of the marketplace,” he said. There will be more patent expirations and opportunities for first-time generics, “but I have less optimism on the biosimilar side.”

“Of 9 biosimilar approvals, we have only 3 launched products,” emphasized Mr. Long, “accounting for just $1 billion in total value of US marketplace in biosimilars.” He was hopeful that biosimilars for Remicade would have “broken the dam,” but this hasn’t happened. “Instead, payers have chosen to take the rebates, not the biosimilars. That resulted in only a 3% marketshare as a result for infliximab biosimilars.”

He noted that the average rebates given to payers and pharmacy benefit managers is 25% for biologics overall. Rebates in the autoimmune area averaged 20%, but payer market research routinely confirms that Janssen’s Remicade® rebates well exceed this figure.

Note: IQVIA is the child of the marriage between Quintiles and IMS.

 

Fujifilm Gains Further Exposure in Biosimilar Partnerships

The biosimilar industry continues to make strange bedfellows. In July 2016, I reported in the Center for Biosimilars that a subsidiary of the Japanese camera maker, Fujifilm, had jumped into the biosimilar field. The Indian pharmaceutical company Biocon announced that it has launched its new insulin glargine biosimilar in Japan. Fujifilm Pharma Co, Ltd was named as the partner in this endeavor to commercialize the product in Japan.

Fujifilm Pharma is a producer of diagnostic and therapeutic radiopharmaceuticals, in addition to contrast media. This makes sense, as the parent is in the imaging business. Medical imaging can be a very natural extension of this activity. But biosimilars?

To reaffirm its strategy, Fujifilm announced a new partnership.  Its Fujifilm Kyowa Kirin Biologics subsidiary will manufacture a adalimumab biosimilar in the EU (filed for approval in the EU only) and will be commercialized by Mylan if approved. There is no information about whether Fujifilm will seek authorization to market this biosimilar in the US down the road.

Fujifilm Kyowa Kirin AstraZenecaTo further its chances of commercializing this biosimilar in the EU, Fujifilm Kyowa Kirin Biologics joined a lawsuit in April 2017 with Samsung Bioepis and its partner Biogen. The lawsuit, filed in the UK, sought to invalidate Abbvie’s two remaining adalimumab patents, and the UK court ruled in favor of the plaintiffs, opening the door to marketing next year in Europe. Fujifilm also has a bevacizumab biosimilar (FKB 238) in phase 3 clinical investigation.

The parent company has over 200 subsidiaries, and it can be complicated to track which ones are directly involved. For example, another Fujifilm company, Fujifilm Diosynth, does contract manufacturing of biologics. Yet, the phase 3 trial being carried out on FKB238 is sponsored by Centus Biotherapeutics Limited, which is a joint venture between Astra Zeneca and Fujifilm Kyowa Kirin Biologics. Centus seems to be involved only with the bevacizumab biosimilar, not with the adalimumab agent. Despite this web of intrigue, Fujifilm is not likely to be overexposed in the biosimilar marketplace. It is also unknown whether their efforts will be affected by the recent difficulties of its partners Biocon and Mylan with getting its pegfilgrastim biosimilar approved. It has been reported that Biocon will also benefit from this latest Mylan collaboration.

How Trump’s Tariffs May Hit Drug Pricing

When President Trump decided to implement tariffs on the imports of Chinese products, he wasn’t talking only about steel and textiles. According to the association representing the generic drug industry, the active ingredients of many pharmaceuticals—including biologics and biosimilars—could also be affected.

Physicians and patients are largely unaware of where their medications are actually manufactured. According to the Food and Drug Administration, President Trump wants tariffsin excess of 80% of the ingredients of drugs used in the US are manufactured beyond our borders. Even if a US facility produces the final agent, the individual components may come from sources outside of this nation.

Each drug comprises active and inactive ingredients (such as precipitates), and many are sourced from different locations. The pharmaceutical industry manages this carefully. Plants in China and India, for example, are popular because of their ability to provide cost-effective compounds that meet the good manufacturing practice (GMP) standards set by the FDA and the European Medicines Agency.

The US Trade Representative published a list of products produced in China tPresident Trump's tariffs may raise drug priceshat could be affected included insulin, growth hormone, antibiotics, amphetamines, immunologic products (e.g., vaccines), diagnostic test kit components, and other medical device materials (e.g., hip and knee implants).

A 25% tariff on imports from China imposed by the Trump Administration would obviously increase the price of the active ingredients of some generics and branded products alike, according to a statement by Jeffrey K. Francer, Senior Vice President & General Counsel, the Association for Accessible Medications. “We are assessing the proposed tariff list of pharmaceutical ingredients and products by the US Trade Representative and its possible impact on manufacturing costs for affordable, FDA-approved generic and biosimilar medicines,” he said. “We are concerned that the proposed tariffs may lead to increased costs of manufacturing for generics and biosimilars and thus higher prescription drug prices for patients in the US.”

Beyond higher costs, another related problem could arise. The pharma supply chain could be disrupted in a trade war with China. Pharmaceutical companies will need to review their options, which may entail requiring new inspections and approvals before changing the source of these needed ingredients. This could result in production delays and perhaps further price increases driven by supply gaps.

The Trump Administration has hit the pharma industry hard for its high prices. Wouldn’t it be ironic if the President himself compounded the problem with this short-sighted solution?

Analyzing FDA Chief Gottlieb’s Remarks—Part 2: FDA and Marketing Exclusivity

Food and Drug Administration Chief Scott Gottlieb, MD, received a great deal of coverage for his recent remarks on providing better access to biosimilars. He seems intent on finding solutions to the underlying problems in delayed biosimilar launches.

He discussed in the interview with CNBC perhaps the most intractable problem: The US biosimilar industry has been severely affected by the reference drug manufacturers filing multiple patent filings and extending their market exclusivity well past the 12 years provided by law. For example, it was hoped that an adalimumab biosimilar would already be marketed, but it now seems that 2022/2023 may be the earliest in US launch because of this “patent maze.”

Dr. Gottlieb agreed that patents filed to protect “small changes in how you manufacturer the drugs” shouldn’t convey an additional 12 years of market exclusivity, and he thinks we’ll see less of these actions in the biologic space going forward. However, “there’s no silver bullet here in terms of trying to really make this market go gangbusters. I think Food and Drug Administrationthis is going to be a slow build. But we’re going to be coming out with…about a dozen policies that I think incrementally will each move the ball in the direction of trying to create more avenues of biosimilar competition.”

One of the underlying challenges is that market exclusivity is described by two components: (1) regulatory (defined by Congress and FDA) and (2) patent law outlined in the US Constitution (and governed by the courts). The first is typified by the Biologics Price Competition and Innovation Act (BPCIA), which specifies 12 years of market exclusivity for the biologic manufacturer.

Originally, the Obama Administration wanted 7 years of market exclusivity but settled for 12 in order to pass the BPCIA. Based on Dr. Gottlieb’s remarks, it seems to be a question of what the FDA can do on its own to effect change. Perhaps the only leverage the agency has today over biologic manufacturers is at the time of approval. I really can’t envision what power it can wield in this fight; does the agency have the authority to cut deals with manufacturers to limit patent applications in exchange for drug approval? It may be that Dr. Gottlieb will try to work with Congress to circumvent the problem through amendments to BPCIA.

Another potential area may be to help biosimilar manufacturers take on the risk of launching before patent disputes are settled. Technically, any biosimilar manufacturer is allowed to launch after its 180-day exclusivity period expires postapproval. Pfizer (and its partner Celltrion) was the first to launch “at-risk.” Although biosimilars have been approved for drugs other than infliximab and filgrastim, manufacturers have been reluctant because of the financial penalties, including profits, which may be awarded by a court to the manufacturer of an originator product. This is why Sandoz has not launched Erelzi® (etanercept-szzs), which gained approval in 2016.

Analyzing FDA Chief Gottlieb’s Remarks: One Challenge With no Easy Solution

Food and Drug Administration Commissioner Scott Gottlieb, MD, undoubtedly understands the threat to a successful biosimilar industry in the US, and his well-reported remarks emphasize some of the key issues. The policies that the FDA Commissioner wants to bring to bear on the multifaceted problem may be harder to implement. In this post, we examine one of those issues.

FDA Commissioner Scott GottliebIn the CNBC interview on Wednesday, he stated, “We’re taking a hard look at how we determine interchangeability so that we can make determinations that biosimilars can be used interchangeably with the brand of drugs.” Dr. Gottlieb correctly pointed out that the interchangeability question is complicated by “variants in lot-to-lot manufacturing of existing biologics and also a lot of variance in the products over time where there’s drift in the sort of formulation of the biologics that are currently on the market.” The variations that manufacturers of any biologics encounter create a “moving target” for not simply a manufacturer trying to prove biosimilarity but also interchangeability. He acknowledged that unexpected clinical effects of these variations have not yet been seen but the potential exists, which is why certain variations are subject to testing by the regulators to address the problem.

Yet, it is not practical to eliminate the lot-to-lot variation that has been seen for decades, sometimes incurred by plant changes or subtly different manufacturing techniques. Does this mean that biosimilar makers will have to test their agent against more samples of the originator biologic and in studies with more patients? For the purposes of proving interchangeability, the variation could undermine confidence in the outcome.

According to the FDA Commissioner, “We’re going to be putting out a set of policies to compel the branded drug makers who have biologics on the market to tighten up their manufacturing, to have less variance of their biologics that are currently on the market.” Preventing this variation in biologic manufacturing sounds like a costly (and possible futile) exercise. Let’s say for example, that one plant must be shut down for a time owing to maintenance; how does one prevent the manufacturer of a compound that demonstrates slightly different structural folding produced at another plant? Only an expert in biologic manufacturing techniques can answer this question.

 

A Test for Adello and for FDA’s Biosimilar Approval Pathway

We are on the verge of a few eagerly awaited decisions by the Food and Drug Administration (FDA). Celltrion and its partner Pfizer expect to hear news on their trastuzumab biosimilar in April, as does Celltrion separately on its rituximab biosimilar. These should make a significant impact on the evolution of biosimilars in the US and on marketshare penetration, but the FDA’s decision around the fourth filgrastim agent from a lesser- known player could be even more important to the industry.

One of the critical areas that differentiate 351(k) from 351(a) biologic licensing applications (BLAs) is that the FDA has emphasized the primary importance of evidence supporting the pharmacokinetic, pharmacodynamic, and structural similarity of the biosimilar to the originator product. In comparison, the standard BLA requires a sufficient catalog of data from phase 1, 2, and 3 clinical trials that point to the efficacy and safety of the biologic. To many in the biosimilar field, the inverted pyramid illustration left is very familiar.

351(k) biosimilar approval requirements

To date, the biosimilars brought to the application or registration process have been evaluated on their physiochemical characterization as well as the results of phase 2 and/or 3 clinical trials in at least one target indication. This is where it becomes interesting: Adello Biologic’s 351(k) application for filgrastim comprises the physiochemical biosimilarity evidence, but in terms of clinical data, only phase 1 studies were performed. That is, these studies included healthy volunteers only. And the studies further demonstrated the comparable pharmacokinetics and pharmacodynamics of this biosimilar and Neupogen®, the originator G-CSF drug.

This decision was not made in a vacuum. The manufacturer consulted with the FDA, as all prospective biosimilar makers do, on the requirements of their data packages. And the FDA accepted the application in September 2017. This fits with the agency’s policy to place ever-increasing weight on the physiochemical data as part of its “totality of evidence” approach. In its 2015 guidance, the FDA stated, “As a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human [pharmacokinetic and pharmacodynamic] data, and clinical immunogenicity assessment.” With Adello’s filgrastim, one assumes that the FDA made the decision that the studies in healthy volunteers was sufficient.

Since Adello would be the second filgrastim biosimilar approved (also the fourth filgrastim on the market), the FDA may decide to dispense with an Advisory Committee meeting to discuss publicly the merits and issues with the agent. However, because this could be the first biosimilar approved without phase 2 or 3 clinical data, the FDA may decide on a conservative course, allowing the clinical community and the public to weigh in.

One could see how the lack of clinical data in actual patients will give pause in an Advisory Committee session. A patient undergoing cancer chemotherapy will likely have a different immunologic status, it can be argued, which may result in immunogenicity problems in real-world use. For agents already marketed in Europe, such issues may be absent and can be considered as part of the totality of evidence. Adello, however, does not market their biosimilar elsewhere.

Even if the Advisory Committee does not recommend (or a slight majority recommends) approval, the FDA could decide to license the drug anyway, in view of its stated policy to get biosimilars to market more rapidly. If this is the case, it would help ensure that R&D costs remain as low as possible for prospective biosimilar manufacturers, without the requirement of performing expensive phase 2 or 3 trials.

The question of whether an Advisory Committee will be held is still unknown. In response to queries, an FDA spokesman offered that the agency had “previously articulated a general expectation that a proposed biosimilar to a given reference product would be discussed at an Advisory Committee meeting if a proposed biosimilar to that reference product had not previously been discussed at an AC meeting. Subsequent proposed biosimilars to a given reference product may also be discussed at an AC meeting if FDA determines that there are specific issues to discuss.” In other words, no one knows. A query to Adello was not answered as of the publication of this article. Any updates will be noted in this space.

 

Is Physician Resistance to Biosimilars Dissipating?

We tend to think of challenges to uptake of approved and marketed biosimilars coming from three areas: (1) the reference product manufacturers, (2) the physicians, and (3) the patients. The patent mazes and rebating strategies characterize the first, and patient advocates’ questions about nonmedical switching describe the last. Physician resistance, however, seems to be on the wane.

I was pleasantly surprised by conversations with health system chief medical officers and medical group administrators speaking about biosimilar implementation and adoption at the annual meeting of the American Medical Group Association last week in Phoenix. If this is any indication, the iPhysician resistance to biosimilars decreasingnitial trepidation of US physicians in using biosimilars in treatment-naïve patients is melting away. Medical society endorsement of the effectiveness of biosimilars and promises of significant cost savings seem to be convincing arguments on physician side. Of course, switching of a reference medication for a biosimilar in a patient established on treatment with the reference product remains another story.

Some of the physicians came to learn about biosimilars rather than share their experiences. They may or may not have been aware of the extensive European experience with specific biosimilar agents and drug classes, but they were willing to accept that (1) if the Food and Drug Administration (FDA) had approved the biosimilar, they expect it to be safe and effective and (2) that extrapolation would not be an issue if FDA approved the label. The use of biosimilars for nonapproved indications would be left up to individual physicians (and payers’ prior authorization systems).

It was clear that the potential of biosimilars to save their patients money was of paramount importance. This may signal a changing view that issues regarding safety and efficacy of approved biosimilars will be preempted by the need to address economic needs in initial prescribing for new patients.

There is also an indication that large medical groups and some health systems are willing to leave the decision making to the Pharmacy and Therapeutics Committee. If the P&T Committee places the biosimilar on the formulary, and it is a savings for their new patients, the biosimilar will be used. That also means that biosimilar adoption at this level will be seriously aided by the use of lower cost-sharing tiers for biosimilars. In other words, a separate biosimilar tier that requires less copayment or coinsurance than the reference product could be a real boost to patient use.

In other biosimilar news…Michigan’s governor has signed legislation making it the 37th state to expand its pharmacy laws to allow interchangeable biosimilar substitution. Now if there were only an interchangeable biosimilar to substitute!

Coherus Biosciences announced that it believes that it will obtain FDA approval and commercial launch for its delayed pegfilgrastim biosimilar in the second half of 2018, along with European approval during the same timeframe.

Pfenex disclosed that it is seeking partners for its own pegfilgrastim biosimilar, in addition to its biosimilar candidate to Lucentis®. Its stock price has taken a steep jump in recent weeks, rising to over $6 a share (from $4) since the beginning of March.

FDA’s Gottlieb to Health Plans: Move Away From Short-Term Rebates on Reference Drugs to Enhance Long-Term Biosimilar Savings

According to Food and Drug Commissioner Scott Gottlieb, MD, the managed care sector’s willingness to accept larger rebates from manufacturers of originator biologics to preserve formulary coverage may seriously hinder the long-term success of the biosimilar industry. And more importantly, the ability to control biologic costs through competition.

FDA Commissioner Scott Gottlieb, MDIn remarks made to a national meeting of America’s Health Insurance Plans’ (AHIP) in Washington, DC, Dr. Gottlieb worried that biosimilar manufacturers may start to believe that “the system is rigged against them.”

In terms of patent litigation, that certainly may seem true. However, Pfizer’s complaint that Janssen is undercutting its discounts by providing plans and insurers additional rebates would seem to be a practice that big pharma has used for years (Pfizer included). Therefore, Dr. Gottlieb is asking payers to turn aside those rebate offers and instead cover the biosimilars, at least for new patients.

He stated that the FDA is “invested in making sure that the new biosimilar pathway works, and that we can help facilitate a robust market for these products. So, we take note when we see market practices that can reduce the incentive for sponsors to invest in the development of biosimilars in the first place.”

Dr. Gottlieb put it to health plans succinctly: “Payors are going to have to decide what they want: The short-term profit goose that comes with the rebates, or in the long run, a system that functions better for patients, providers, and those who pay for care…Do they want to continue to benefit from monopoly rents today, or help generate a vibrant biosimilar market that can help reset biologic pricing—and drug pricing more generally— through competition.”

He suggested that payers help increase biosimilar uptake by lowering or waiving copays for biosimilars or removing prior authorization requirements when biosimilars can be prescribed. “FDA has a strong interest in seeing the biosimilar market grow,” he reiterated, “but some of that is going to be up to the choices you all make.”

More Clinical Study Evidence That Biosimilar Switching Carries a Low Risk

A literature review published this past weekend in Drugs reaffirms what most parties interested in biosimilars suspect—that switching from a reference product to biosimilar is not a significant clinical concern. Biosimilar switching was not generally associated with poorer outcomes.

The study evaluated the results of 90 clinical studies comprising more than 14,000 patients with 14 diseases or conditions. The authors from Novartis (and its Sandoz subsidiary), the Oregon Medical Research Center, Rocky Mountain Cancer Centers, IBD Center of Humanitas Clinical and Research Hospital (Milan), and Avalere Health stated that “the great majority of the publications did not report differences in immunogenicity, safety, or efficacy [as a result of biosimilar switching]. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone.” In addition, they reported, “Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar.”

In this evaluation, the biosimilars tested included those for infliximab, epoetin, filgrastim, growth hormone (which has not been considered a biosimilar in the Ubiosimilar switchingS), etanercept, and adalimumab. Infliximab was the subject of the majority of the clinical studies.

Of the 90 studies, two were outliers, suggesting potential safety issues associated with biosimilar switching. One was described as a 2016 retrospective study of a claims database from Turkey, which found a much higher discontinuation rate with the infliximab biosimilar compared with originator product in patients with rheumatoid arthritis.

The authors correctly note that the vast majority of the studies reviewed involved a single biosimilar switch, and that multiple switches may result in additional safety signals. However, they also point out that “patients have already been exposed to de facto multiple switches for many originator biologics when product quality attributes changed after one or more manufacturing process modifications were introduced.”

The question arises as to whether multiple switch studies are truly necessary outside of the requirement to prove interchangeability between a biosimilar and a reference product. There is a practical reason for doing so—the possibility (actually, the likelihood) of a patient enrolling in a new health plan one year, which covers the biosimilar but not the reference product. If the patient’s health plan changes once again one or two years later, that person may well be required to switch back to the reference product or yet another biosimilar.

This will heighten the importance of collecting real-world evidence and accumulating more experience outside of the clinical trial environment in terms of switching. Efforts such as those at the Biologics and Biosimilars Collective Intelligence Consortium should fill this gap over the next several years.

 

Celltrion and Inflectra, Mylan and Botox, and a Biosimilar Blooper

The second quarter is expected to be rife with news regarding Food and Drug Administration approval decisions on a biosimilar for rituximab and two pending applications for trastuzumab. Although biosimilars have not generated much news of importance lately, we wrap up the week with some items of interest.

Celltrion and Pfizer's Inflecta biosimilar form of infliximabFirst, Celltrion estimates that it will conclude a phase 1 pharmacokinetics trial of its infliximab biosimilar (Inflectra®) in a new subcutaneous route by July 2018. This could potentially be important, if successful, because Inflectra, the originator product Remicade®, and Renflexis® are only available for administration through intravenous infusions (normally at the physician’s office, given over the course of multiple hours). One of the attractions of other anti-TNF products for use in Crohn’s disease and other immunologic disorders (e.g., adalimumab, ustekinumab) is the availability of subcutaneous autoinjectors or prefilled syringes, allowing it to be given at home, and much more rapidly. This could potentially widen the infliximab market a bit.

Second, Mylan announced an agreement with the California-based company Revance Therapeutics to develop and commercialize a biosimilar form of onabotulinumtoxin A or Botox®. The popular injectable botulinum toxin derivative has been used since Allergan's Botox the 1990s for cosmetic indications as well as for muscle spasms and even for the prevention of chronic migraine. Interestingly, Revance, a biotech development company, is currently focused on another neuromuscular modulator, daxibotulinumtoxinA, principally for cervical dystonia (phase 2) and plantar fasciitis (phase 1).

Finally, the New England Journal of Medicine published a biosimilar blooper on Wednesday, when author Richard G. Frank, PhD, of the Department of Health Care Policy, Harvard Medical School, attempted to provide some perspective on the slow availability of biosimilars in the US. He wrote that 7 biosimilars were now available for use; this of course is a misstatement. Nine biosimilars have been approved for use in the US but only 3 New England Journal of Medicine's biosimilar blooper(2 for infliximab) were actually marketed. Surprisingly, this made it past the N Engl J Med reviewers and editors. Dr. Frank also emphasized that “secrecy about manufacturing processes” was a significant barrier; however, this is probably less a problem than prospective biosimilar manufacturers trying to obtain samples of the reference product for characterization and comparison during preclinical and clinical development.