Jackie Syrop

The FDA issued a long-awaited draft guidance for the biopharmaceutical industry that outlines the agency’s criteria for demonstrating that a biosimilar is interchangeable with a reference product—that it can be substituted for a reference product by a pharmacist without requiring intervention of a prescribing healthcare provider if state regulations allow pharmacy-level substitution. Interchangeability isn’t required for FDA approval of a biosimilar or for commercial adoption of a product, but it is an important advantage in the US marketplace. Prior to the release of this guidance it was not known how the agency wished drug sponsors to prove interchangeability.

Comments on the guidance must be received within 60 days of January 17, 2017, before the FDA makes its interchangeability rules final.

 explains the type and amount of data and information needed to support a demonstration of interchangeability with the reference drug. It specifies that pharmaceutical sponsors of proposed biosimilars should submit data from switching studies or other studies, and how they should be designed to demonstrate that the biosimilar is interchangeable with a reference drug.  

The FDA states that the main purpose of a switching study or studies is to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch. The switching study should evaluate changes in treatment that result in two or more alternating exposures to the proposed interchangeable product and to the reference drug. In addition, the guidance states that a switching study is to determine a biosimilar product’s interchangeability with a reference product that is licensed for use in US clinical settings; thus, establishing interchangeability with a product that patients will not receive in the United States would generally not be appropriate.

Analysts have suggested that the new guidance will make it harder to achieve an interchangeable designation than the industry had hoped. Switching studies are more complicated than many of the studies already in process, and will be required to include two exposure periods per product. In addition, the guidance suggests that the process of gaining a designation of interchangeability will be a long one.  

It is likely that sponsors of biosimilars have been receiving informal guidance from the FDA as they work to bring their products through the approval process, but it is not clear whether drug developers are using study designs that would potentially meet the new standards expressed in the interchangeability draft guidelines.

The guidance notes that because of the complexity of biosimilars, the agency will consider interchangeability on a case-by-case basis. While the FDA will generally not consider postmarketing data, in certain specific circumstances such data from a licensed biosimilar may be a factor to consider concerning what data are needed to support a demonstration of interchangeability.

A perspective piece by Leah Christl, PhD, Associate Director for Therapeutic Biologics and Lead of the Therapeutic Biologics and Biosimilars Staff in the 

 provides a detailed explanation of how the FDA approaches the issue of interchangeability to ensure there are rigorous approval standards, as for products administered more than once. “There is no single data package that will work for all proposed interchangeable products,” she writes. “With this in mind, we recommend that applicants developing a proposed interchangeable product meet with FDA early in their development process to discuss their plans.”

Articles

FDA Releases Draft Guidance on Biosimilar Interchangeability 

The European Union’s regulatory agency, the EMA, has approved over 20 biosimilars, 4 of which are indicated for psoriasis and psoriatic arthritis. Each EU member country has its own approach to 

In Spain, physicians affiliated with the Psoriasis Group of the Academia Española de Dermatología y Venereología (AEDV) published an opinion article stating that the organization celebrates the incorporation of biosimilars into the treatment regimens for psoriasis and psoriatic arthritis because the new drugs are likely to decrease the high cost of biologic therapies, which have substantially improved the treatment of these conditions.

 In Spain, the high cost of biologics has prompted debate on the economic sustainability of the country’s public health system, so the combination of effectiveness and lower prices presented by biosimilar drugs has created great interest. Physicians, patients, and the pharmaceutical industry have all taken part in the Spanish national debate, much as they did years ago when generic drugs were introduced.

The AEDV states that the use of biosimilars should not imply a reduction in therapeutic efficacy, patient safety, or the prescriber’s freedom of choice. But they note that biosimilars, while representing savings, do not appear to offer advantages over reference biologics. Decisions about which drug to prescribe should not be based on economic considerations alone but rather scientific evidence, they say.

An important concern expressed by physicians prescribing a biologic or a biosimilar for psoriasis and psoriatic arthritis is that they find the right treatment for patients with moderate to severe chronic plaque psoriasis who have failed to respond to, are intolerant of, or have a contraindication for other systemic therapies, including cyclosporine, methotrexate, or psoralen plus UV-A therapy. Although this is the approved indication for both the reference infliximab biologic and the approved biosimilars, the AEDV is concerned that the approval of infliximab was supported by data from clinical trials in patients with rheumatoid arthritis (RA) and ankylosing spondylitis, and 

 specifically patients with psoriasis and psoriatic arthritis. This is referred to as  “extrapolated indications,” and the AEDV calls for clinical trials involving psoriasis and psoriatic arthritis patients of the biosimilars to the degree possible in order to obtain direct information about efficacy and safety in these patients.

The decision to prescribe a biosimilar should be assessed on a case-by-case basis, the AEDV states, and patients must agree with the choice. In Spain, the decision about the interchangeability of biosimilars for the reference biologic is left to the physician. Biosimilars may not be automatically substituted for reference biologics.

The AEDV states that to best ensure patient safety, the biosimilar must submit to a pharmacovigilance program that is as vigorous as that applied to the reference biologic. Namely, each drug must be traceable and identifiable at all times to track possible adverse events.

Finally, the AEDV endorses clarity and precision in patient and prescriber information for biosimilars so that the prescriber and patient can make informed decisions about the acceptability of these medications. “We must take steps to inform and teach those concerned,” the AEDV states, and ideally, information should reflect consensus formed before the new drugs are used routinely.

Hernandez GC, Puig L, en representacion del Grupo de Psoriasis de la AEDV. The use of biosimilar drugs in psoriasis: a position paper. 

Biosimilars for Psoriasis: Spain's Dermatologists Weigh In 

The FDA has extended the review period of the New Drug Application (NDA) for baricitinib, Eli Lilly/Incyte Corporation’s once-daily investigational oral rheumatoid arthritis (RA) treatment, an additional 3 months beyond the Prescription Drug User Fee Act’s 1-year goal for reviewing NDAs. The additional time was needed to review more data submitted by Lilly in response to information requests made by the agency.

Some analysts considered baricitinib a potential “blockbuster” because it has shown clinical superiority over Humira (adalimumab), has a strong safety profile, and is an oral, rather than injection, 

RA treatment that was expected to be close

 to launch and possibly available before Humira biosimilars enter the market.

The NDA for baricitinib was submitted to the agency for review in January 2016. However, the FDA determined that submission of additional information constituted a Major Amendment to the NDA, resulting in the 3-month extension. Baricitinib was also submitted for regulatory review in the European Union and Japan in early 2016. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use issued a positive opinion of the drug in December 2016, recommending its approval. If approved in Europe, it would be marketed there as Olumiant. The drug is also being studied in phase II trials for atopic dermatitis and systemic lupus erythematosus, and a phase III trial for patients with psoriatic arthritis is expected to begin in 2017.

Baricitinib is an oral JAK (Janus kinase) inhibitor 

in development for inflammatory and autoimmune diseases

. There are four known JAK enzymes, and JAK-dependent cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a range of inflammatory conditions, according to Lilly. “We will continue to work closely with the FDA throughout the review process and we believe that baricitinib has the potential to be an effective treatment choice, especially for those patients for whom current therapies are not adequately addressing their disease,” said J. Anthony Ware, MD, senior vice president, product development, and interim president of Lilly Bio-Medicines.

FDA Extends NDA Review Period for New RA Treatment Expected to Compete with Humira

Boehringer Ingelheim’s adalimumab biosimilar candidate to Humira, BI 695501, has been accepted for regulatory review by both the FDA and the European Medicines Agency (EMA).

The applications for FDA and EMA approvals are supported by top-line results from the completed Phase III study of BI 695501 that were  announced in October 2016, which was  conducted in patients with active rheumatoid arthritis (RA), according to Boehringer Ingelheim. [www.boehringer-ingelheim.us/press-release/boehringer-ingelheims-adalimumab-biosimilar-candidate-shows-similar-efficacy-and] The results of the study showed that BI 695501 met the clinical study efficacy end points to establish equivalence with Humira in patients with active RA and also met the secondary end points for the efficacy, safety, and immunogenicity of BI 695501 versus Humira.

The Phase III study was a randomized, double-blind, parallel arm, multiple dose, active comparator study in 645 patients diagnosed with moderate to severe active RA who were treated with methotrexate. Each participant was randomized to either BI 695501 or Humira every 2 weeks for 48 weeks. Efficacy was measured in patients with RA by ascertaining the proportion of patients with RA who met American College of Rheumatology 20 (ACR20) criteria at week 12 and week 24 compared with baseline.

If approved, BI 695501 can offer a high-quality, economically sustainable treatment option to patients with inflammatory diseases, said Martina Flammer, Vice President, Clinical Development and Medical Affairs, Specialty Care, at Boehringer Ingelheim, and would be a critical milestone for the company as it seeks to expand treatment options for patients with biosimilars.

Boehringer Ingelheim Adalimumab Biosimilar Accepted for Review by FDA and EMA

Pfizer announced positive results from the company’s comparative, confirmatory 

study for the investigational monoclonal antibody PF-06410293, a potential Humira (adalimumab) biosimilar, saying that the study met primary objectives by demonstrating equivalent efficacy as measured by the American College of Rheumatology 20 (ACR20) response rate at week 12 in adult patients with moderate to severe arthritis.

The ACR20 response is defined as ≥20% improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (according to the disability index of the Health Assessment Questionnaire [HAQ]); and C-reactive protein (CRP).

The REFLECTIONS B538-02 trial is evaluating the efficacy, safety, and immunogenicity of PF-06410293 compared with Humira, with each being taken in combination with methotrexate when administered subcutaneously. REFLECTIONS B538-02 is a multinational, randomized, double-blind, two-arm, parallel group equivalence study conducted in 597 patients who have had an inadequate response to methotrexate therapy. The 

began in June 2015 and is expected to be completed in December 2017.

Sumant Ramachandra, MD, PhD, MBA, Head of Research and Development, Pfizer Essential Health, said the positive study results for PF-06410293 build on the company’s robust biosimilar pipeline, which consists of eight distinct biosimilar molecules in mid- to late-stage development and several others in early-stage development.

The newest data from PF-06410293 represent Pfizer’s second proposed biosimilar for inflammatory conditions and third proposed biosimilar pipeline molecule to report positive top-line results within the past 4 months. 

Pfizer Announces Positive Trial Results for Potential Humira Biosimilar 

Are biosimilars that can potentially compete with Humira, Enbrel, and Remicade going to be able to pose a threat to the “Big Three” rheumatoid arthritis (RA) biologics?

What about other new products currently on the horizon for the treatment of RA? 

—expected to be upwards of $20 billion by 2020--with special attention to biosimilars and new RA medications waiting in the wings and weighs in what the future might bring. 

RA affects approximately 4.9 million people globally (1.3 million Americans). The biologics Humira, Enbrel, and Remicade are usually used as a second-line treatments when patients do not have an adequate response to the first-line treatment for RA, usually disease-modifying antirheumatic drugs (DMARDs) like methotrexate. But about a third of RA patients have an inadequate response to DMARDs, so biologics for RA can be used in conjunction with DMARDs to increase clinical remission rates, or in some cases, as a first-line treatment. Most biologics marketed for RA are tumor necrosis factor-alpha (TNF-alpha) inhibitors, which have demonstrated high efficacy when combined with DMARDs, and strong safety profiles, with adverse events and serious adverse events similar to those seen with methotrexate therapy.

In the RA market, biologics have the highest rate of sales growth: over 92% of global RA sales come from biologics. Yet, as 

notes, biologics are not the first-line treatment for RA, so DMARDs and other therapies have a higher volume but generate less than 10% of total sales because of their low pricing.

The top-selling biologics (including all approved indications) globally were AbbVie (Humira) with a third of the market, Amgen (Enbrel) and Johnson & Johnson (Remicade) with 17% each, and Rituxan (Genentech) with 14% of the market (Rituxan’s main sales are for cancer). Simponi (Janssen) sales, at 6% of the market, is the next largest seller among biologics. Thus, the “Big Three” are far above the rest of the biologics. But by 2018 there should be a biosimilar of each of the Big Three drugs on the US market, says 

after which it’s expected that sales in the RA market will begin to contract as more biologics and biosimilar enter the market and put pricing pressure on the industry.

So far, however, only one biosimilar has launched: Pfizer’s Inflectra, a biosimilar for Remicade. 

 believes that Inflectra will likely negatively affect the sales of all biologics, not just Remicade. But Amjevita, an approved biosimilar for Humira, is not expected to launch in the US until 2018 at the earliest as it appears to be caught up in litigation delays, as is Erelzi, an approved Enbrel biosimilar. Other potentially approvable biosimilars are still in Phase III development.

there looms approvals of new RA treatments  immediately on the horizon that show high clinical efficacy even as monotherapies, especially for patients who failed prior TNF-alpha inhibitor treatments. The closest to launch among these is baricitinib (Lilly/Incyte), which may be a “blockbuster” because it is an oral treatment and has shown clinical superiority over both Humira and Xeljanz, the other Janus kinase (JAK) inhibitor on the market. It has a strong safety profile. The deadline for the FDA to review the NDA for baricitinib is January 19, 2016, so unless there are delays, baricitinib could be launched this year. There are many other drugs for RA in the US pipeline as well. 

In the near future, Pfizer--the first to market with a Remicade biosimilar—will likely benefit from being able to generate sales while the other biosimilars fight it out in court. But once baricitinib enters the market, all of the RA products will feel it, especially if baricitinib can position itself ahead of TNF-alpha inhibitors. Johnson & Johnson may stop some of the losses  caused by Inflectra if its new RA products in the pipeline launch, but it will likely see a decline in market share. AbbeVie should do well because Humira’s longer effectiveness remains a selling point, and the company is fighting Amgen’s Humira biosimilar in court. AbbeVie’s new RA drug in the pipeline is expected to help keep revenues flowing should baricitinib be the blockbuster it may become. Finally, Amgen appears to be the least well positioned in the RA market because Amjevita, its biosimilar to Humira, is tied up in a legal fight, and the company has no products in its pipeline for RA besides biosimilars. 

What Lies Ahead for the Big Three RA Drugs?

Although US regulators continue to struggle with the interchangeability of approved biologics and biosimilars, one policy researcher believes that there is already enough evidence to prove that biosimilars are equivalent to biologics and should be used interchangeably. Canadian drug policy researcher Alan Cassels, of the University of Victoria, British Columbia, Canada, wrote in the January 2017 issue of 

that a large body of evidence already demonstrates the interchangeability of approved biosimilars, and this proof ought to outweigh pharmaceutical companies’ interests and open the door to 

As Cassels explains, biosimilars already on the market in Europe are estimated to be 10% to 70% cheaper than brand-name counterparts. A recent audit by the Royal College of Physicians suggests that if all UK patients being treated with a monoclonal antibody received biosimilars, the UK’s National Health Service would 

 and still realize the same health outcomes. 

The audit found that infliximab biosimilars were equally effective and safe compared with the originally patented medication, Remicade. Cassels also points to the widely discussed study in the August 2016 

 by G. Caleb Alexander and colleagues at the Johns Hopkins Center for Drug Safety and Effectiveness, which concluded that biosimilars of Remicade appeared to be just as safe and effective as Remicade, and were far less expensive.

 (Inflectra), it was not designated as interchangeable with Remicade, so in some states pharmacists will not be able to switch patients from Remicade to Inflectra. To date, none of the four biosimilars to be approved by the FDA are interchangeable.

The interchangeability of biosimilars could have a big impact on pharmaceutical spending worldwide. Biologics such as Remicade and Enbrel account for approximately a fifth of all US drug spending. Global spending on biologics is predicted to reach $221 billion in 2017. Because approximately $71 billion in patented biologics will have their patents expire by 2020, Cassels explains, there is a race to produce biosimilar products to sell at a discount and capture the market.

So what’s holding biosimilars back? The lack of interchangeability.

Attitudes about biosimilars and interchangeability vary around the world. In the European Union, the approval process for biosimilars involves comparing biosimilars with their reference medicines to show that there are no significant differences between them. However, the EMA does not make recommendations about whether a biosimilar can be used interchangeably with its reference medication. Rather, the EMA suggests that patients should speak to their doctor and pharmacist if they have questions about switching from one biological medicine to another. Taking a different approach, Australia’s drug advisory committee recommends that biosimilars are suitable for substitution at the pharmacy level.

In the United States, health insurers are interested in introducing biosimilars to control drug costs. But drug companies are simultaneously “

 to protect sales of branded biologic drugs while also developing biosimilars of their own.” Cassels says the defensive strategies include lobbying medical professionals and the public that biosimilars cannot be interchangeable because there are too many variations related to their complexity, and that the FDA alone must designate interchangeability to ensure patient safety --criticisms he calls unsupported and intended to slow down or derail the use of biosimilars and prevent health systems and patients from saving money on these new less expensive, effective, and comparable therapies.

Cassels concludes, “Pharma and the drug lobby are weak in their efforts to discredit biosimilars and imply lower levels of safety and tolerability compared with their originator products. Research suggests no substantive outcome differences between the use of originator biologics and their biosimilar counterparts, and arguments against their effectiveness and safety fall flat.”

Should Biosimilars Be Interchangeable with Biologics?

Biopharmaceutical company Oncobiologics is up against the world’s largest biotech and pharma companies in its mission to produce biosimilars that will be marketed at significantly lower prices than the original drugs, and which will be designated as interchangeable as well.

That’s the message Oncobiologics Chairman, President, and CEO Pankaj Mohan sent in a recent interview conducted at the JP Morgan Healthcare Conference 2017 in San Francisco, reported by 

. “We don’t believe that giving a 20% to 30% discount is going to move the needle in terms of healthcare savings,” he said. To make a real impact on the cost of drugs, the reduction should be much deeper: 

Oncobiologics is a clinical-stage biopharmaceutical company focused on identifying, developing, manufacturing, and commercializing complex monoclonal antibody biosimilar therapeutics. Its Humira (adalimumab) biosimilar, ONS-33010, received its first approvals for global 

Mohan has previously been quoted as saying biosimilars should cut up to 50% off reference product prices because taking 15% to 20% off the price of the original drug is not a significant enough saving for payers, who are looking for saving 40% to 50%--especially for a product like 

Mohan believes that a key element to the company’s success marketing its biosimilars will be not just FDA marketing approval but a designation of interchangeability—which has not been granted to any of the four currently FDA-approved biosimilars. He said the FDA (and the European Medicines Agency [EMA]) are willing to work with biosimilar sponsors on a more effective approval process, and that although the FDA’s guidance on interchangeability is not yet available, Oncobiologics has been able to work with and learn from the FDA to create a program that the agency could eventually approve. Oncobiologics received approval to combine studies on both biosimilarity and interchangeability for ONS-33010 into a single Phase III trial.

Mohan noted that Oncobiologics eliminates inefficiency and waste by combining its operations into a single, integrated facility in Cranbury, New Jersey, rather than establishing manufacturing and product development in two different countries. He attributes these practices to a faster production cycle, another factor that he expects to be critical to the company’s success and ability to market biosimilars. Finally, acknowledging the tremendous resources available to the companies marketing reference medications that allow tremendous investment in continuing legal fights to extend market exclusivity, Mohan calls for greater progress to be made in preventing “evergreening” of drug patents beyond their initial window of exclusivity.

He believes this trend began in 2016, with movements against the high cost of drugs and health care: “I would say it's an irreversible socio-political movement.”

We'll feature the latest biotechnolology "movers and shakers"--and how they are impacting the biosimilars industry.

Biotech Movers and Shakers: Eye on Oncobiologics

Pfizer announced that the Centers for Medicare and Medicaid Services (CMS) will cover the cost of the company’s biosimilar Inflectra (infliximab-dyyb) for Medicare enrollees as a Part B-covered drug. Inflectra was approved by the 

 as a biosimilar to Janssen Biotech’s Remicade (infliximab) for reducing signs and symptoms in patients with rheumatoid arthritis, adult and pediatric Crohn’s disease, adult ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and chronic severe plaque psoriasis.

The CMS reimbursement price, which took effect January 1, 2017, is a 15% discount to the Wholesale Acquisition Cost (WAC) of Remicade. The WAC does not include discounts to payers, providers, distributors, and other purchasing organizations.

Inflectra is the first biosimilar monoclonal antibody, and the second biosimilar, to become available in the United States. The FDA’s approval of Inflectra as a biosimilar to Remicade did not include interchangeability with the reference drug; pharmacists cannot substitute Inflectra for Remicade without a physician’s instructions.

Pfizer announced the launch of the Pfizer enCompass program, 

 and patient support program offering coding and reimbursement support for providers, co-pay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.

Pfizer also announced the availability of pricing for 340B hospitals, a drug pricing program for eligible healthcare organizations that serve as safety net providers, including Medicare/Medicaid Disproportionate Share Hospitals, children’s hospitals, Ryan White clinics, and State AIDS Drug Assistance Programs.

Inflectra began shipping to wholesalers in late November 2016, and can now be ordered from wholesalers across the country.