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DRugwatch Blog > February 2012 > Finally! The FDA Issues Draft Guidance for Biosimilars

Finally! The FDA Issues Draft Guidance for Biosimilars

Matt KileenContributor: Andrew Merron, Biosimilars Advisory Service Director at BioTrends Research Group

On 9th February 2012, the FDA finally published draft guidance addressing the over-arching requirements for biosimilar medicines to gain approval in the United States. The publication has been met with considerable relief throughout the biosimilar industry after much anticipation and speculation, although provides only general guidance and little detailed information.  Back in September 2011, the FDA hinted that their guidance for biosimilar medicines could be just a matter of days or weeks away. However, with no formal guidance published, the industry grew impatient. The only other publically available information from the FDA concerning biosimilar requirements were published in August in a New England Journal of Medicine article.

At the start of 2012, many biosimilar manufacturers were hoping for some clear guidance from the FDA on biosimilar product development, and the wait has been extensive compared with their European colleagues.  The European Medicines Agency (EMA) first published over-arching guidelines on biosimilar medicines in 2005, more than six years before the FDA, and there are currently 14 biosimilars approved for use in Europe by the EMA. Despite the frustration over the lack of any guidance from the FDA, Hospira is the first company to initiate a pivotal Phase III trial for a biosimilar in the US even prior to the availability of FDA guidelines. The first patient was enrolled onto the clinical trial in January this year.

It is now nearly two years since the necessary legislation was signed into law allowing for biosimilars to enter the US market. On the 23rd March 2010, President Obama passed the Patient Protection and Affordable Care Act (PPACA); this act amended the Public Health Service Act (PHS Act) through the creation of the abbreviated pathway (also known as the 351(k) route) -allowing biosimilar approval. The 351(k) pathway is provided as part of the Biologics Price Competition and Innovation Act (BPCI Act) within the PHS.

The guidance that the FDA has issued comprises three documents: scientific guidance, quality guidance, and commonly asked questions and answers for the industry. Currently, the guidance is still in a draft version, and the FDA will welcome any public input prior to finalizing these documents. In addition, there is no product-specific guidance for individual classes of biologics. Nevertheless, we expect that eventually the FDA will issue product-specific guidance for demonstrating biosimilarity.

New Guidelines

Overall, there are no major surprises in the draft guidelines compared to what we had expected. Essentially, the FDA is drawing on similar themes already presented by the EMA’s over-arching biosimilar guidance documents. The FDA clearly presents three over-arching themes:

  • A stepwise, risk-based approach to biosimilar product development including strong recommendation for early consultation with biosimilar sponsors
  • Justifications are required from biosimilar sponsors for their pre-clinical and clinical development strategies; also, explanations are sought for any differences seen between the biosimilar and the reference product
  • A ‘totality-of-the-evidence’ approach to approving biosimilars in the US on a case-by-case basis

The stepwise approach to demonstrating biosimilarity is critically important to streamline clinical trial design through later stages of evaluation. The scientific guidelines propose assessment of biosimilarity through three main steps:

1. Firstly, analytical studies are required. This rigorous structural and functional comparability exercise is important in order to smoothly proceed to the following steps. State-of-the-art techniques should be employed to assess the biosimilar and reference product. 
2. Secondly, because subtle changes in functionality between a biosimilar and the reference product may not be detected in analytical studies, the biosimilar sponsor is required to perform further studies. Therefore, animal studies (including the assessment of toxicity) may be required.
3. Thirdly, a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics and pharmacodynamics) are required to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed. Because product-specific guidance is not yet available, discussion of specific end points are not included in the current draft guidelines.  However, the clinical safety and effectiveness studies should select clinically relevant end points which can detect meaningful differences.
Indication Extrapolation Possible but Interchangeability is Challenging
Importantly, as we expected, the FDA is allowing for indication extrapolation for biosimilars as long as the extrapolation is founded on scientific justification. Indication extrapolation may be allowed assuming the biosimilar sponsor has considered potential differences in each indication with respect to the mechanism of action, pharmacokinetics, biodistribution, and toxicities. Despite the FDA allowing a biosimilar to undergo indication extrapolation, our research has suggested that physicians are unwilling to automatically accept and prescribe a biosimilar without specific clinical data in that indication. This suggests that clinical trials will be required in most indications in order to gain access to all indications for which the reference product is approved.

The draft FDA guidelines also consider interchangeable biosimilars. An interchangeable biosimilar must demonstrate a higher standard of interchangeability over a non-interchangeable biosimilar product. This greater standard includes demonstrating that the biosimilar produces the same clinical result as the reference product in any given patient and the risk of switching between the biosimilar and the reference product (in terms of safety or diminished efficacy) is not greater than using the reference product alone. The questions and answers document highlights that this will be a difficult barrier to overcome; although an interchangeable product may be considered eligible for automatic substitution at the pharmacy level.

Quality Guidelines

The quality guidelines also released on the 9th February for biosimilar products focused on physiochemical considerations for demonstrating biosimilarity, including the expression system, manufacturing process, immunochemical properties, impurities, stabilities, and reference standards.

New Era of US Biosimilars is Imminent

The guidance is welcomed by industry and we now anticipate the confirmation of the guidelines after any public comments and expect product-specific documents to then be considered. Based on the growing number of biosimilar players, and the impending patent expiries for major blockbuster biologics, the future of the biosimilar industry can really start to gain momentum despite a somewhat sluggish start over the past five years in Europe. Once biosimilar versions of the commercially compelling products are developed, and biosimilars finally enter the US, growth in sales of biosimilar products will be significant from 2015 through 2020.

Despite the high burden, development of biosimilars represents a significant cost-saving opportunity for State-sponsored healthcare systems.  In an age of increased austerity, lower cost biosimilars have the opportunity of saving in excess of $10 billion across the seven major pharmaceutical markets in 2020 - a highly attractive proposition.  The publication of the draft guidelines by the FDA last week (while there is still much more we are waiting for) represents a major milestone in bringing these lower-cost products to market in the US.

The Biosimilars Advisory Service Director, Dr. Andrew Merron, will be hosting an analyst call describing the implications of these recently published guidelines on the 27th February. Learn more.
Posted on: 2/14/2012 3:06:54 PM | with 0 comments

Tags: Andrew Merron, Biosimilars

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Post title: Statins: Add Them to the Drinking Water?
Post date: 8/18/2014 1:07:35 PM
Post Summary: Contributors: Tim Blackstock and Stefanie Hoffart

Statins are one of the most commonly prescribed drugs, and Pfizer’s Lipitor (atorvastatin) still holds the record for the highest peak sales of any prescription drug. The general consensus of thought leaders in the field of lipid disorders and CVD prevention is that the benefits of statins outweigh the risks, although this applies more for secondary prevention that primary prevention.
Post text: Contributors: Tim Blackstock and Stefanie Hoffart

Statins are one of the most commonly prescribed drugs, and Pfizer’s Lipitor (atorvastatin) still holds the record for the highest peak sales of any prescription drug. The general consensus of thought leaders in the field of lipid disorders and CVD prevention is that the benefits of statins outweigh the risks, although this applies more for secondary prevention that primary prevention. However, the widespread use of statins has long generated an undercurrent of concern over the potential for negative effects in such a large population. Various issues have been raised, ranging from their lack of benefit in women through to safety concerns, and the debate has been fired up by the release of new guidelines recommending even broader use of these agents. In November 2013, the ACC and AHA published new guidelines that included a recommendation for statin therapy in patients with an estimated ten-year risk of atherosclerotic cardiovascular disease (ASCVD) of 7.5 percent or higher. Then, in July 2014, the UK’s National Institute for Health and Care Excellence (NICE) released guidelines recommending that patients with a ten-year risk of CVD that exceeds 10 percent should be treated with atorvastatin 20 mg. NICE estimates that if half of the lower risk primary prevention group take statins, an extra 4,000 deaths from heart attack could be saved, and 8,000 strokes and 14,000 non-fatal CV events could be prevented.

However, both sets of guidelines have received mixed feedback. In a letter to NICE, UK experts expressed concerns about a variety of topics like the medicalization of healthy individuals and the true levels of adverse events. For them, the benefits are simply not convincing enough to justify five million people being started on a drug for life. NICE argued their case in a letter of their own. Various experts and professional organizations have also expressed concerns over the U.S. guidelines, including a group from the Mayo Clinic that has just published their opinion here. Debate also continues over the safety of the class: new-onset diabetes, myopathy, and cognitive problems are all associated with statin use. But, as is the case with a lot of scientific research, the quality varies, and different studies have found different results. This has led to a dispute over safety research published in the BMJ, which, because of the common use of these drugs, has been picked up by the lay press.

So, how will all of this affect prescribing and sales of statins? Will we see the public health equivalent of them being added to the drinking water? The guidelines’ recommendations are based on a wealth of solid evidence showing CV benefit with statin use, and encourage a discussion between physicians and patient over taking statins. In addition, the statins are now almost all available as generics making them inexpensive and more accessible. However, the fact that the class is almost totally genericized is likely to mean there will be little impact on sales, despite the increasing prevalence of dyslipidemia. Moreover, the ongoing controversy about the guidelines, combined with the slow and often limited adoption of guidelines by the average physician, suggests to us that there will not be a mass shift in physician practice. You can lead a physician to statins in the water, but you can’t make them drink.

Stefanie Hoffart, M. Sc., is a Research Associate and Tim Blackstock, M.B. Ch.B., M.Phil., is a Business Insights Analyst in the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

In-depth analysis of type 2 diabetes, with accompanying epidemiology driven sales forecast models, are presented in Decision Resources Group’s Type 2 Dyslipidemia Pharmacor, available here. A new edition of this product is planned for November 2014.
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Post title: The Biosimilar Train Leaves the Station, Only to Face an Uphill Climb
Post date: 8/13/2014 11:23:09 AM
Post Summary: Contributor: Chris Lewis

Faced with the onslaught of high-cost specialty drugs—a reality brought to the fore by the high-priced hepatitis C drug Sovaldi—many plan sponsors no doubt heaved a sigh of relief at the first U.S. filing for approval of a biosimilar last month.
Post text: Contributor: Chris Lewis

Faced with the onslaught of high-cost specialty drugs—a reality brought to the fore by the high-priced hepatitis C drug Sovaldi—many plan sponsors no doubt heaved a sigh of relief at the first U.S. filing for approval of a biosimilar last month.

But for every shred of hope pinned on the ability of biosimilars to moderate the rising specialty drug trend, there’s a counterbalancing dose of reality that gives payers pause when planning for meaningful cost savings from these biologic imitators.

Managed care pharmacists and benefit specialists were cautioned about the limitations of the biosimilar movement during a panel session at the Pharmacy Benefit University conference near Chicago in early August.

What made the discussion particularly topical was the announcement a couple of weeks earlier that Sandoz, the generic pharmaceuticals division of Novartis, filed the first U.S. license for a biosimilar under the FDA’s biosimilar pathway. The approval process for filgrastim—which references Amgen’s neutropenia drug Neupogen—is expected to take at least 10 months, said Stephen Cinchy, managing director of Monarch Specialty Group, a healthcare consulting firm.

The Affordable Care Act directed the FDA to develop a pathway for development of biosimilar versions of biologically produced pharmaceuticals. Although the guidelines are still in draft form, companies are free to pursue biosimilar development through what’s known as the 351(k) pathway. This path is untested in the United States and greatly differs from the generic pathway for traditional drugs.

Because biologics are large, complex molecules that are manufactured in living cells, they cannot be copied identically, as is the case with traditional small-molecule drugs. Biosimilars must meet the standard of being highly similar to the originator product, with no clinically meaningful difference to the patient, explained Gary Okano, director of biotechnology engagement for Amgen.

Aside from defending Neupogen from biosimilar competition, Amgen is among the pharmaceutical companies racing toward biosimilar development to meet the demand for lower-cost specialty drugs. Amgen is pursuing biosimilar alternatives to high-profile rivals Humira and Remicade in the rheumatoid arthritis space.

Based on biosimilar products expected to launch through 351(k), and their impact on referenced branded drugs, Decision Resources Group’s Biosimilars Advisory Service forecasts that healthcare savings will reach nearly $9 billion annually in the United States by 2022.

However, payers cannot count on the up-to-80-percent savings in drug costs they have experienced with generics. Because biosimilars face much higher costs of production—including the requirement of clinical trials—the projected price difference between biosimilars and their reference products are more in the 15 percent to 30 percent range. That’s not to mention the expensive legal patent and market access battles that lie ahead.

Monarch’s Cinchy told conference-goers that companies marketing the innovator products are ready to pull out the big guns to keep biosimilars at bay. “The list of tools and weapons that they’re going to be essentially assembling to respond to biosimilars is deep and wide,” he said.

Plan sponsors can expect that companies will sweeten the rebate pot to protect the market share of innovator products. “Many of the innovator products today have rebates,” Cinchy said. “If a biosimilar comes forward with a price discount, but no rebate, the net difference, if I push through a biosimilar, might be zero or something much less than the face value of that discount.”

Meanwhile, companies are defending their branded specialty drugs by introducing new formulations—which Cinchy termed “bio-betters”—that make the drug more attractive to the patient, for instance, through less-frequent dosing.

There are other unknowns that constrain the potential of the biosimilar market, including safety concerns, the yet-undetermined naming convention for biologics, and whether states will pass laws to allow pharmacies to automatically substitute reference products with approved biosimilars.

In addition, getting patients to embrace biologic alternatives will take a huge educational effort, considering payers have struggled to get them to embrace generics. Physicians appear ready to prescribe biosimilars, according to Decision Resources Group. “The majority of U.S. specialists that we’ve surveyed expect to use biosimilars, but the rate and depth of their acceptance is highly variable by specialty and even the specific biologics that they prescribe,” said Kate Keeping, DRG senior director of biosimilars research.

Whatever the obstacles, the biosimilar train has left the station and is gaining speed. It may deliver plan sponsors from the imposing crush of specialty drug costs, and they will be sure to get on board so as not to miss any opportunity to tame costs that are rising by double-digit rates each year.

Follow Chris Lewis on Twitter @ChrisLewisDRG
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Post title: AstraZeneca Strengthens Its Position on Respiratory Therapeutics
Post date: 8/12/2014 4:17:19 PM
Post Summary: Contributor: Sangha Mitra

Last month, AstraZeneca took a major step to build up its respiratory franchise by striking a deal for the commercial rights to Almirall’s respiratory portfolio. The transaction, which is expected to complete by the end of 2014, could be worth up to $2.1 billion. It comprises an initial upfront payment of $875 million to Almirall and up to $1.22 billion in additional payments tied to performance, both regulatory and commercial, milestones.
Post text: Contributor: Sangha Mitra

Last month, AstraZeneca (AZ) took a major step to build up its respiratory franchise by striking a deal for the commercial rights to Spanish group Almirall’s respiratory portfolio. The transaction, which is expected to complete by the end of 2014, could be worth up to $2.1 billion. It comprises an initial upfront payment of $875 million to Almirall and up to $1.22 billion in additional payments tied to performance, both regulatory and commercial, milestones. AZ CEO Pascal Soriot had previously identified the respiratory therapy area as one of his key growth drivers, in an attempt to prove AZ can deliver value to shareholders independently, when the company rejected Pfizer’s takeover bid earlier this year. These new assets will provide AZ immediate access to on-market revenues as well as create long-term value through strategic fit of Almirall’s complementary drug pipeline and inhaled device capabilities for the treatment of both asthma and chronic obstructive pulmonary disease (COPD). In the short-term, the deal gives AZ access to Almirall’s share of revenue from the currently marketed long-acting muscarinic antagonist (LAMA), Eklira/Tudorza. AZ will also acquire selected European and Canadian rights to this drug from Almirall while U.S. rights will remain with Actavis. These sales will contribute to AZ’s sales at a time when respiratory sales begin to decline due to the loss of patent protection for its blockbuster drug, Symbicort (a fixed-dose combination of budesonide and formoterol).

Almirall's decision to sell-off its respiratory franchise may seem surprising, since respiratory was its leading therapeutic area and accounted for 30percent of its 2013 sales. However, the high cost of large clinical trials and heavy marketing expenditure ensure that it would be challenging for Almirall to compete against industry heavyweights such as GlaxoSmithKline and AZ. Therefore, selling the franchise to the more-experienced AZ, while retaining a stake in its development, is a notable win for Almirall.  The sale of these products and programs will allow the company to reduce costs and risk while retaining an important economic interest in the franchise’s potential success. In addition, Almirall will be able to move more aggressively in other specialty areas of focus including dermatology, where the company seeks to become a global player and can build up this business with its substantially increased financial resources.

Unfortunately, while Almirall’s assets will certainly grow AZ’s respiratory franchise, the overall impact on the company may not be enough to thwart shareholders from agitating for the board to accept a sweetened takeover offer from Pfizer or another potential suitor. Pfizer desperately needs a promising acquisition to boost growth, and AZ - due to its size, tax inversion opportunity and valuation - remains a compelling target.

Sangha Mitra is a business insights analyst on the Immune and Inflammatory team at Decision Resources Group.
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Post title: AMG-416 on the Horizon: What Does this Mean for Other Renal Therapies?
Post date: 8/1/2014 11:23:09 AM
Post Summary: Contributor: Jihan Khan

AMG-416 is being developed as a calcimimetic agent administered intravenously, which would be the first IV calcimimetic to the SHPT market. It is designed to bind and activate the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH.
Post text: Contributor: Jihan Khan

On July 17th 2014, Amgen announced positive Phase 3 results for AMG-416 (formerly known as velcalcetide) for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis (HD).

First, a bit of background on SHPT – it is a disorder that develops early as an adaptive response to declining kidney function when the parathyroid glands increase the production of parathyroid hormone (PTH) in an effort to maintain normal levels of serum calcium and phosphorus. Ultimately, excess PTH production proves inadequate for maintaining normal serum calcium and phosphorous levels, which in turn can lead to significant clinical consequences. AMG-416 is being developed as a calcimimetic agent administered intravenously, which would be the first IV calcimimetic to the market. It is designed to bind and activate the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH.

Amgen obtained AMG-416 as part of the acquisition of KAI Pharmaceuticals, Inc. in July 2012 and these are the first results to be reported from the Phase 3 program - analysis of the data presented shows that the study met primary and all secondary endpoints. 75.3 percent of patients achieved a > 30 percent reduction from baseline in PTH compared with 9.6 percent in the placebo arm, a statistically significant result. Secondary endpoints included the percent change from baseline in serum phosphorus (P) concentration (mean changes of -9.63 percent and -1.60 percent among patients in the AMG-416 and placebo arms, respectively) and corrected calcium (cCa) concentration (mean changes of -6.69 percent and 0.58 percent among patients in the AMG-416 and placebo arms, respectively). Both of these secondary endpoint results were statistically significant.1 

The TreatmentTrends®: Nephrology (US) Q2 2014 report published in June 2014 focuses on the management of SHPT and provides insights into physician perceptions of SHPT, based on primary market research of 203 U.S. nephrologists, and I thought I would share some findings from the report that highlights the potential opportunity for manufactures in this space. The report asks physicians for their perceived use of PTH modifiers such as nutritional vitamin D (NVD) products, active vitamin D (AVD) products, and calcimimetic agents such as Sensipar, in addition to other areas of nephrology, including phosphate binders, ESAs and IV/oral iron, but we will discuss these other areas at a later point in time.

In the PTH modifier market, Amgen’s Sensipar is indicated for the treatment of SHPT in patients with CKD on dialysis and is taken orally. According to Amgen’s 2013 annual report, Sensipar generated sales in excess of $1 billion in 20132 and according to Amgen’s recent press release, total Sensipar sales increased 15% for the second quarter of 2014 versus the second quarter of 2013.3 In TreatmentTrends®: Nephrology (US) Q2 2014, surveyed nephrologists reported that nearly 40 percent of their HD patients and over 30 percent of their peritoneal dialysis (PD) patients were on Sensipar. However, after reviewing AMG-416’s product profile, surveyed nephrologists estimated 36 percent of their dialysis patients as likely candidates for AMG-416 treatment, based on AMG-416’s Phase 2 data alone. We are looking forward to how the positive findings from the Phase 3 trial will change nephrologists’ perceptions of AMG-416 in our TreatmentTrends®: Nephrology (US) Q3 2014 report, scheduled to publish in September 2014.

Assuming FDA approval, it will be interesting to see if AMG-416 stands to gain patient share at the expense of Sensipar, given the more convenient dosing option with AMG-416 for dialysis patients. Or, perhaps this was Amgen’s plan all along to develop a new product to extend the patent life of their PTH modifier business given Sensipar’s patents are expiring in 2015 and 2016 in the U.S.2

The report also asks nephrologists a series of barriers to increased Sensipar use and patient non-compliance was cited second most often by surveyed nephrologists, and for patients who receive dialysis treatment three times a week in the United States, things are looking positive for AMG-416 as an effective calcimimetic agent that can be administered intravenously with HD to help treat SHPT, which may improve compliance similar to the high perceived compliance of ESAs in the dialysis setting.

Renal treatments are interrelated and should use of calcimimetics increase with greater compliance with AMG-416, it will interesting to see what impact in use, if any, it will have on some of the other renal medications, most predominately phosphate binders and AVD. Today, we know that Sensipar may also be sometimes used to treat phosphorous, calcium and PTH and perhaps binder and AVD use will ultimately be impacted as well with greater use of calcimimetics. The chart from TreatmentTrends®: Nephrology (US) Q2 2014 below shows some of the reasons why nephrologists use Sensipar.

Results from a head-to-head study evaluating AMG-416 compared to Sensipar is expected next year.4

JIhan Khan, Ph.D. is a business insights analyst on the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

Amgen news release, July 17, 2014 http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1948573
2 Amgen 2013 annual report and 10-K, March 27, 2014 http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-reportsannual
3 Amgen press release, July 27, 2014 http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle_Print&ID=1952691&highlight=
4 Head-to-head study of AMG 416 and cinacalcet (Phase 3), July 24, 2014 (last verified) http://clinicaltrials.gov/ct2/show/NCT01896232?term=AMG+416%2C+sensipar&rank=1
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Post title: Sandoz Beats the Crowds to File First Biosimilar in the United States
Post date: 7/25/2014 10:27:16 AM
Post Summary:   Contributer: Kate Keeping

 The moment that we (biosimilars enthusiasts) have all been waiting for has finally arrived! Sandoz has become the first company to disclose filing of a biosimilar application in the United States. On July 24, 2014, Sandoz announced that the FDA had accepted its application for approval of filgrastim (referencing Amgen’s Neupogen) via the previously unused biosimilar (aka 351[k]) pathway.
Post text:   Contributer: Kate Keeping

 The moment that we (biosimilars enthusiasts) have all been waiting for has finally arrived! Sandoz has    become the first company to disclose filing of a biosimilar application in the United States. On July 24, 2014, Sandoz announced that the FDA had accepted its application for approval of filgrastim (referencing Amgen’s Neupogen) via the previously unused biosimilar (aka 351[k]) pathway.

Is it likely to be approved?

Yes! Sandoz has been selling the same filgrastim product in over 40 countries, under the brand name Zarzio, for several years with no major unexpected safety events reported. Oncologists that we have surveyed in Europe who use the drug say it has the same safety and efficacy as Neupogen and it is the most-preferred biosimilar filgrastim. On top of that, Sandoz claims to be the class leader with 30 percent volume share, so there are no red flags about the product from the current market experience.

From a regulatory point of view in the United States, there is still an element of uncertainty; the FDA has not provided product-specific guidance on what it expects in a biosimilar filgrastim dossier (unlike the EMA), but the U.S. agency’s general guidance is similar to that of the EMA’s and Sandoz will have had several meetings with the FDA throughout its development program. Sandoz has tested the drug in four Phase I trials in healthy volunteers plus a Phase III trial in breast cancer patients receiving myelosuppressive chemotherapy using U.S.-sourced reference product. We assume Sandoz is seeking approval for all five of Neupogen’s indications, so perhaps the biggest question mark remains over whether the FDA will permit full indication extrapolation (approving a biosimilar for reference-brand indications that the biosimilar has not been tested in). We continue to believe that this is highly likely given that the mechanism of action of filgrastim is the same across its five approved indications, and because there is a well-defined pharmacodynamic marker for its efficacy.  

The only other potential obstacle to market entry would be Neupogen patents. One of the downsides for companies choosing to file through the biosimilar pathway, rather than opting for the full BLA route (351[a]), is that they must submit their entire dossier to the reference sponsor’s legal team. They must then embark on a series of meetings designed to resolve any outstanding patent issues in parallel with the FDA’s regulatory review. The material patent for Neupogen expired in December 2013, enabling Teva to launch its own filgrastim product, Granix (tbo-filgrastim), via the full BLA pathway in 2013. Assuming that Sandoz has managed to avoid infringing any of Amgen’s other patents, we see no reason that Sandoz should not become the first company to launch a biosimilar in the United States in the next 10 to 12 months.

What will it be called?

This is a particularly topical question. Recently, the FDA has been going somewhat ‘off piste’ with its biologic naming. The prefixes that the FDA has attached to USANs for drugs like Teva’s Granix (tbo-filgrastim), Roche’s Kadcyla (ado-trastuzumab emtansine), and Sanofi’s Zaltrap (ziv-aflibercept), are not endorsed by the WHO (the body that issues INNs), but were adopted by the FDA to avoid prescribing errors. However, it is yet unknown whether the FDA is expecting to use the same prefix system for biosimilars because its long-awaiting biologic nomenclature policy is yet to be published, although it is planned for this year. Therefore, we still do not know what the non-proprietary name will be for Sandoz’s filgrastim; we assume that Sandoz will adopt a brand name in the U.S. to aide pharmacovigiliance, perhaps Zarxio which was recently registered as a trademark for the company.

What’s the commercial opportunity?

A lot of excitement in the biosimilars industry at the moment is focused on monoclonal antibodies; these really do hold the potential to cause a dramatic shift in the commercial potential of the biosimilars industry given that several multi-billion dollar MAbs will go off patent soon. Filgrastim is not one of these. However, the reference product, Neupogen, generated $1.2B in U.S. revenue last year, which presents a reasonable opportunity for biosimilar competitors. By five years post launch of follow-on filgrastim products, we believe Neupogen could have lost half of its market share.

What’s the competition like?

As mentioned, Teva has already launched a filgrastim product (Granix) in the United States. Although this molecule was approved as a biosimilar in Europe and Japan, it was approved via a full BLA in the United States (for historical rather than strategic reasons). Granix’s head start on Sandoz’s filgrastim, could be dented by a couple of important differences between a biosimilar and full BLA-approved brand. 

Firstly, Granix was ineligible for indication extrapolation and therefore is only approved for reducing neutropenia in non-myeloid malignancy patients receiving myelosuppressive chemotherapy. In order for Teva to expand Granix’ label, the company would need to invest in further clinical trials, impacting the profitability of the drug and potentially its pricing flexibility. We expect Sandoz’s filgrastim to have the same label as Neupogen.

Secondly, Medicare reimbursement rules will be more favorable to Sandoz’ biosimilar filgrastim than Teva’s Granix. According to the Average Sales Price +6% rule, the value of reimbursement for a biosimilar will be its average selling price plus 6 percent of the reference brand’s price. However, because Granix was not approved via the biosimilar pathway, reimbursement is calculated as the average selling price plus 6 percent of its own price, which is approximately 20 percent less than Neupogen. Hence, the reimbursement value will likely be lower for Granix than the biosimilar, incentivizing use of Sandoz’s product.

But the true juggernaut facing both Sandoz’s biosimilar filgrastim is Amgen’s Neupogen. Decades on the market and tens of billions in historical revenue means not only are multiple generations of physicians familiar with Neupogen, but Amgen may have greater flexibility to price Neupogen defensively than many of the manufacturers of MAbs being targeted by biosimilars companies.

Granix and Neupogen are unlikely to be the only competition that Sandoz will face. Hospira already sells a filgrastim biosimilar (marketed as Nivestim) in Europe and Australia. The company has intimated that it will seek approval in the United States, although a timeline of additional trials, if any, has not been revealed. Apotex, on the other hand, has already completed a U.S. bridging study for its filgrastim biosimilar (Grastofil) that was in-licensed from the Indian company Intas. With at least five companies fighting it out for share of the U.S. filgrastim market, there is likely to be pressure on price, and on developing effective differentiation strategies to convince physicians and payers which filgrastim is best.

When will more biosimilars be filed in the United States?

We expect a small flurry of U.S. biosimilar applications now. The next filing could also be from Sandoz; back in April, the company indicated that it was preparing to file pegfilgrastim for approval in the United States as well. There is an outstanding patent on the reference product, Amgen’s Neulasta, but this will expire in October 2015, so by the end of 2015, Sandoz could have two U.S. biosimilars in its portfolio.

Celltrion has also disclosed U.S. filing plans for its infliximab biosimilar, known as Remsima in most markets. This application could be more complicated however; Celltrion has challenged J&J’s patents ahead of filing, but assuming this suit is unsuccessful, if Celltrion were to gain FDA approval next year, launch would be delayed until patent expiry in 2018.

The third likely early entrant to the U.S. biosimilar market is Hospira. The company’s biosimilar epoetin alfa (Amgen’s Epogen / J&J’s Procrit) trials have taken longer than expected in the U.S., but an application is now slated for late 2014 or early 2015.

2015 will be a landmark year for the U.S. biosimilars industry!

On August 7, 2014, Kate will be hosting an analyst call entitled Coming to America: Sandoz Files the First Biosimilar in the United States, covering this topic in detail. Contact us for more information on how you can attend.

Kate Keeping is senior director of biosimilars research at Decision Resources Group.
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