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Industry News

June 2018

Learn about recent developments across the biosimilar industry. Visit our News Archive to find out more.

GLOBAL: AbbVie focuses on potential Humira® successor as biosimilar competition looms   +

AbbVie has announced positive top-line results from its Phase 3 SELECT-COMPARE clinical study that compared upadacitinib, an oral (non-biologic) Janus kinase (JAK) inhibitor, versus placebo, and versus Humira® (adalimumab) in patients with rheumatoid arthritis (RA).

  • In SELECT-COMPARE, upadacitinib (15 mg, once-daily) met both primary endpoints, with 71% of patients achieving ACR20* and 29% achieving clinical remission at Week 12.
  • All ranked secondary endpoints were also met, with significantly more patients on upadacitinib achieving low disease activity (45%) and ACR50* (45%) at Week 12 compared with those treated with adalimumab (29% for both endpoints).
  • Upadacitinib significantly inhibited radiographic progression at Week 26 compared with placebo.
  • The safety profile of upadacitinib was consistent with previously reported results, with no new safety signals detected.

The data from this study continue to support AbbVie’s goal of finding a new foothold in the RA space after it loses its patent exclusivity for Humira®, allowing adalimumab biosimilars to enter the market. According to a recent statement, AbbVie plans global regulatory submissions for upadacitinib for RA later this year.

*Symptomatic improvement based on American College of Rheumatology criteria (20% or 50%).

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GLOBAL: Analysis of global medical literature shows exponential increase in biosimilar research   +

The quality and quantity of worldwide research on biosimilars is increasing exponentially, according to the first published bibliometric analysis of biosimilars, by Hernández-Vásquez et al, in the Journal of Pharmaceutical Policy and Practice. Bibliometric analysis is used to objectively measure current research into a subject and its international scientific influence. The researchers found that the number of documents published on biosimilars had risen from three in 2004 to 521 in 2016 (P<0.001). Terminology associated with biosimilar publications was also observed to change over the years. Terms such as “legislation,” “structure,” “protein,” and “generic” dominated in the earlier range of years examined, whereas more recently, specific diseases and drugs were the top terms used, mirroring the overall trends associated with biosimilar development.

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GLOBAL: Global report highlights unequal access to biologics and biosimilars for IBD   +

The European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA), an umbrella organization that represents 34 patient associations around the world, has released a new report on healthcare inequities among nations and regions. In the report, the EFCCA identified disparities in access to biologics and biosimilars for the treatment of inflammatory bowel disease (IBD), identified from a survey of 32 national associations.* While the originator biologics adalimumab (Humira®) and infliximab (Remicade®) are approved to treat IBD diagnoses in all the participating countries, some countries have notable regional differences in availability and reimbursement, and some state a range of pre-conditions for treatment. Biosimilar infliximab (Inflectra®), is approved to treat IBD in 27 nations (84%) but, again, coverage is sometimes partial and 15 nations state various pre-conditions for treatment. Furthermore, the same molecule, when marketed as Remsima®, had additional differences in availability and coverage compared with the Inflectra® brand.

*Associations participating in the survey represented Argentina, Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Malta, New Zealand, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, and the United Kingdom.

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USA: Biosimilar state legislation may thwart federal law   +

During a session at the Academy of Managed Care Pharmacy’s (AMCP) Annual Meeting, held April 23–26, 2018, in Boston, MA, USA, Reginia Benjamin, Director of Legislative Affairs for the AMCP, provided an in-depth look at state legislation on biosimilars. As well as summarizing the current status of such legislation, she highlighted how state laws may undermine and confound the intent of the US Food and Drug Administration (FDA). The history of state legislation was briefly summarized as follows:

  • 2013: The first legislation required pharmacists to notify prescribers by phone or fax within a specified time-period if they intended to dispense a biosimilar. There were also labeling requirements and additional record-keeping that were not required for other drugs dispensed.
  • 2014: New laws added provisions that notification could be achieved by adding a note into an electronic health record, so pharmacists would no longer have to phone or fax.
  • 2015: An entry into a pharmacy benefit manager’s system that was accessible to the prescriber was deemed as acceptable notification.
  • 2016: Notification and labeling requirements arose for dispensing an interchangeable biosimilar.
  • 2017/2018 (to date): No additional provisions.

Currently, 41 states and Puerto Rico, have laws addressing biosimilars and interchangeable biosimilars. The following requirements vary across states:

  • Notice to the patient required prior to dispensing a biosimilar.
  • Approval by the patient required prior to dispensing.
  • A timeframe for notice that varies from 24 hours up to 10 days.
  • Additional labeling requirements and record-retention timeframes.
  • Level of liability for a pharmacist who dispenses a biosimilar or interchangeable biosimilar (compared with that incurred by dispensing a different drug).

Significant issues and challenges with current state legislation were highlighted as follows:

  • State laws are not consistent with the Biologics Price Competition and Innovation Act’s (BPCIA) intent, which is to support price competition and innovation in the market, balanced with consumer interests.
  • Generally, there is no authority for pharmacists to substitute a biosimilar deemed interchangeable by the FDA for the reference product without the approval of the prescriber.
  • States do not use the FDA’s definition of interchangeable biosimilars. Instead, they refer to language in the original BPCIA. State laws have also given interchangeability a two-part definition: A biologic product determined by the FDA to meet the standards of interchangeability set forth in the BPCIA, or a biologic product determined by the FDA to be therapeutically equivalent as set forth by the FDA’s Orange Book – even though the Orange Book is for small-molecule drugs and not biologics.
  • Generally, there is no recognition of the FDA’s Purple Book, which lists licensed biologic products and whether they have approved biosimilars/interchangeable biosimilars.
  • States will probably continue to enact laws that are not consistent with the intent of the BPCIA and will likely change the BPCIA definitions and create barriers to dispensing.
  • Patient and prescriber confidence in these FDA-approved products may be hindered by restrictive state laws.

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USA: US biosimilar utilization management strategies are often clinically flawed, report finds   +

Healthcare consultancy Avalere has issued a new report concluding that many biosimilar utilization management strategies, including preferential formulary design and step therapy, are not only impeding the uptake of biosimilars in the US but are also clinically flawed. The report’s authors assessed commercial plan coverage and formulary design concerning biosimilars for the top 25 payers, covering approximately 189 million lives. Of the plans reviewed, 18 had available documents related to infliximab and its biosimilars:

  • Ten plans required use of the reference infliximab, Remicade®, first (alone, or in combination with a disease-modifying antirheumatic drug [DMARD]). Only one plan required the use of the biosimilar (Inflectra®) first, and only one plan allowed either Remicade® or Inflectra® to be used first-line.
  • Two plans required 12- or 14-week treatment periods to demonstrate treatment failure.
  • Four plans have different policies for the use of infliximab biosimilars in different approved indications.

The report highlights that, in many cases of step therapy that require a patient to start with an originator biologic, the biosimilar of the same product will only be covered if the patient fails to respond adequately to the originator. This demonstrates a fundamental lack of understanding that a biosimilar is highly unlikely to work if its originator does not and contradicts the European League Against Rheumatism’s (EULAR) recommendations that switching to another drug – not to a biosimilar of the same drug – is needed in the case of treatment failure. The authors write that, while it is to be expected that payers will act to protect their short- to medium-term financial interests, the extent to which such biosimilar utilization policies are necessary or clinically appropriate is questionable.

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USA: US patient group calls for Federal Trade Commission to investigate AbbVie’s biosimilar deals   +

The US patient advocacy group Patients for Affordable Drugs (P4AD) has called on the Federal Trade Commission (FTC) to examine whether a so-called “pay-for-delay” deal struck between AbbVie (makers of Humira®) and biosimilar developer Samsung Bioepis violates anti-competitive and antitrust laws. The deal is the second such agreement AbbVie has made; the first was with Amgen. In both cases, the agreement holds off the US market entry of adalimumab biosimilars until 2023, giving AbbVie five more years free of biosimilar competition. “AbbVie is using pay-for-delay deals to keep a cheaper product off the market and patients are the victims. We believe it is illegal and anti-competitive, and we are asking the FTC to step in and protect patients from AbbVie’s price hikes,” said David Mitchell, President and Co-founder of P4AD. The statement added: “Humira® is incredibly expensive. Over the past 5 years, the price has more than doubled. Its most recent price increase of 9.7% in January of this year (2018) will cost the US healthcare system $1.2 billion. We have patients all over the country who are hurt by these pay-for-delay deals.” P4AD has also encouraged patients to write to their Senators in support of changes that would put an end to such settlements, and says that, to date, more than 1200 patients have written to show their support.

In response, AbbVie has stated: “AbbVie’s settlements with Amgen and Samsung Bioepis are in no way pay-for-delay arrangements. AbbVie is not paying Amgen or Samsung Bioepis, and in fact both Amgen and Samsung Bioepis will be paying royalties to AbbVie once their adalimumab biosimilar products launch in the [United States].”

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USA: Research highlights evolving approaches to biosimilars in the US   +

At the Academy of Managed Care Pharmacy’s (AMCP) Annual Meeting, held April 23–26, 2018, in Boston, MA, USA , a number of research teams presented posters relevant to the US adoption of biosimilars.

  • A survey sent to health plan executives and pharmacy benefit managers (with 77 respondents) found that specialty pharmacy products continue to transition from fixed co-pays to percent co-pays, and more plans now cover physician-administered products under the medical benefit (44.1%, up from 15.2% in 2016). Only 53.1% of respondents expect biosimilars to be used across all of the reference product’s indications (down from 59.5% in 2016), and 44.9% expect to restrict approved indications (up from 31% in 2016). One quarter of plans expect that a biosimilar will be the only product available for some indications. Among the respondents, 45.1% expected less than a 10% savings from biosimilars in 2018, 47.1% expected a 10–20% saving by 2020, and 58% expected greater than a 20% saving by 2025.
  • Researchers from Magellan Rx Management and Magellan Health sought to analyze the impact of a “least cost alternative” cost-of-care program for ophthalmic injections administered under the medical benefit for the commercial and Medicare Advantage members of a regional health plan. A new fee schedule was implemented for three reimbursed intravitreal anti-VEGF drugs: aflibercept (Eylea®), ranibizumab (Lucentis®), and bevacizumab (Avastin® – an off-label use but commonly utilized in practice due to the significantly lower price). Reimbursement for bevacizumab was increased from market rate to a margin comparable to the other two products. After a year, annualized savings were $2.9 million for commercial plans, and $885 thousand for Medicare Advantage plans. The researchers say that such programs will become especially important when cost-saving biosimilars for these products reach the US market.
  • Researchers from the Sharp Rees-Stealy Medical Group in San Diego, California, USA, described their experience of working closely with physicians on biosimilar adoption. Since physicians commonly report that they have concerns about comparative response to biosimilars, safety, patient preference, and the limited data on antibody cross-reactivity between a reference and a biosimilar product, the authors found that “it is tough to pursue an aggressive strategy such as enforcing substitutions to biosimilars.” Instead of mandatory switching, the group is adopting a collaborative program requiring physicians to prescribe a biosimilar in treatment-naïve patients, and to consider a biosimilar during renewal of every prior authorization for a given therapy, though these protocols will not apply to patients with uncontrolled disease or known immunogenicity. Physicians will retain the right to disallow biosimilar substitution and safety and efficacy data will be collected on an ongoing basis.

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USA: Oncologist sees biosimilars playing a key role in the Oncology Care Model   +

An oncologist at a South Carolina practice has described the role that biosimilars can play in achieving the objectives of the Oncology Care Model (OCM). The OCM, a reimbursement model developed by the Centers for Medicare and Medicaid Services’ (CMS), Center for Medicare and Medicaid Innovation, allows oncology practices to enter into payment arrangements that include financial and performance accountability for episodes of cancer care. The model is intended to improve health outcomes and produce higher quality care at the same cost or a lower cost to Medicare. Kashyap Patel, MD, CEO of Carolina Blood and Cancer Care, reported that, as his practice has begun to implement OCM, it has moved 100% of its patients to biosimilar filgrastim (Zarxio®) from the reference filgrastim, Neupogen®. With an approximate 15% difference in cost between the two products, the change has saved the practice – and Medicare – valuable resources, and Patel sees the potential for savings to be even greater once biosimilar anticancer therapies reach the US marketplace. With the cost savings that his practice has achieved so far under OCM, Patel says that his clinic has been able to institute drop-in hours for patients who have any health concerns, even concerns that aren’t related to their cancer treatment. “The patients love it,” he said, and the practice has been able to refer patients to other specialists to address comorbidities that are impacting their overall health.

To date, Patel says that his patients have not had concerns about using biosimilar filgrastim instead of the originator. He explains that, in his rural South Carolina practice, many patients “are still using flip phones” and aren’t particularly concerned about the nuances of biosimilarity or the technicalities of the biosimilar approval pathway. Instead, they care about whether a treatment has been approved by the US Food and Drug Administration (FDA) and whether it is effective in treating their condition. “If I were practicing in Manhattan or in Beverly Hills,” he said, “these conversations might be different,” but even when anticancer biosimilars like trastuzumab and bevacizumab reach the clinic, Patel expects that mutual patient–provider respect will be the most important factor in patients’ acceptance of biosimilar drugs. Provider education, as well as patient awareness, remains a massive unmet need in bringing biosimilars into the clinic. In Patel’s view, it’s not just the oncologist who has to become more knowledgeable about biosimilars: nurses are a cornerstone of patient care. “Patients spend 6 hours with the infusion nurse while they may spend 15 minutes with me,” he said, adding that it’s human nature for some patients to be reticent about asking their physician questions about their treatment and may prefer to ask a nurse. As the anticancer biosimilars begin to make their way into the clinic, Patel plans to work on enhanced nurse education to help support and reassure patients as they undergo treatment.

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EUROPE: European regulators are open to novel strategies in biosimilar development, review finds   +

While the European pathway for biosimilar approval is older and more developed than that of the United States, regulation of biosimilars is still evolving. A new review published in the British Journal of Clinical Pharmacology explains that novel strategies are emerging in the development of biosimilars for the European market, and that regulators seem willing to consider these alternative strategies when scientifically justifiable. Approval of biosimilars appears possible even in cases where European Medicine Agency (EMA) guidelines have not been strictly followed. The authors examined European Public Assessment Reports (EPARs), as well as information from PubMed and clinical trials databases, on 17 EMA-approved biosimilars and made the following observations:

  • Submission of fewer data than officially required
    In the case of an approved enoxaparin sodium biosimilar, the product sponsor did not conduct Phase 3 studies (which were specified in product-specific guidance), only 20 healthy volunteers were included in a pharmacodynamic study, and no intravenous route of administration was included in a study. “In the case where a sponsor has a strong scientific rationale for a specific development [program], regulators in Europe still seem to be open minded to alternative development strategies, even for cases where a product‐specific guideline has already been issued,” write the authors.
  • Variable choice of study population
    Two biosimilars of etanercept have been approved in Europe, one on the basis of studies in patients with rheumatoid arthritis (RA), and one on the basis of studies conducted in patients with plaque psoriasis. The product-specific guidance on monoclonal antibodies indicates that the “most sensitive” patient population and clinical endpoint should be used in development, and the Committee for Medicinal Products for Human Use (CHMP) has indicated a preference for the RA population for etanercept. It is unclear why plaque psoriasis was selected by one of the two sponsors, but the product achieved approval nonetheless.
  • Non-inferiority studies used in place of equivalence studies
    Generally, biosimilar product sponsors are asked to show equivalence, not non-inferiority, of their products versus the reference drugs. However, in the cases of the two approved insulin glargine biosimilars and an approved rituximab biosimilar, the sponsors submitted data from non-inferiority studies.
  • Post hoc choice of equivalence margins
    In the case of an approved rituximab biosimilar, efficacy using the mean change from baseline in the 28‐joint Disease Activity Score was evaluated, and an equivalence margin was chosen after the fact and justified by historical data. The product sponsor also provided a second study with the same primary endpoint, using the same equivalence margin. It is not clear why the first study was presented as the pivotal efficacy study, though the choice of margins can be discussed and agreed upon with the EMA.
  • Increasing use of bridging studies, adaptive designs, and multiple switches
    While crossover designs remain the most frequently used study designs, six of the applications that the authors examined, used bridging studies – comparing the biosimilar with both a US-approved and EU-approved originator product – which may point to global development programs for the proposed biosimilars. Typically, these studies include 3-period crossover designs. Adaptive designs, in which there is no fixed sample size at the beginning of the trial, are also on the rise, with such designs reported in EPARs for approved biosimilars of teriparatide, insulin glargine, and adalimumab. Switching studies – such as one conducted for an approved etanercept biosimilar – are growing in popularity as well, likely because such studies are forward-looking approaches to addressing US regulatory requirements for demonstrating interchangeability.

The authors conclude that there is high variability among submitted applications for biosimilars, and that the EMA is open to considering approaches that deviate from official guidelines, provided there is appropriate scientific justification for this and sufficiently convincing totality of data to support a demonstration of biosimilarity.

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EUROPE: Sandoz takes unorthodox route to boosting biosimilars in the UK   +

Sandoz, the generics arm of Swiss drugmaker Novartis, has been closely collaborating with Jatinder Harchowal, Chief Pharmacist at London’s Royal Marsden Hospital, the UK’s leading cancer center, to shift roughly 80% of eligible patients from originator rituximab to a biosimilar version in only 6 months, achieving an estimated £80 million in savings for the UK’s National Health Service (NHS). Yet rather than continuing to use Sandoz’s biosimilar, the Royal Marsden has now chosen one manufactured by Napp Pharmaceuticals. Sandoz’s decision to invest in the project with no guarantee of an immediate commercial return highlights the potential it sees in a market, which it says will be worth $14 billion by 2020. Tim de Gavre, the company’s UK head, said: “We have a vested interest in creating a sustainable environment around biosimilars.” Building confidence among doctors and patients through such initiatives is seen as crucial to the uptake of biosimilars, especially in oncology. Emphasizing that the work could not have happened without the resources Sandoz was able to commit, Mr Harchowal said: “We felt that to engage the clinical mind and heart, you had to really make sure people understood how biosimilars were offering exactly the same clinical outcomes, with the same safety profile, but at a much cheaper cost.” The shift in the NHS’s stance is already evident. In the last financial year, it has saved £170 million by using three biosimilars – well on the way to a goal set by Simon Stevens, head of the health service in England, to save £300 million from this approach by 2021.

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EUROPE: European Biosimilar Medicines Conference highlights continued success with biosimilar adoption   +

Biosimilar experts from across the European Union (EU) have showcased how rapidly biosimilars have gained market share, in contrast to US and Canadian markets. Keith Ridge, Chief Pharmaceutical Officer at National Health Service (NHS) England, told attendees at the 16th Annual Biosimilar Medicines Conference in London, that the UK has seen increasing uptake of rituximab, infliximab, and etanercept biosimilars, particularly in London. For instance, a biosimilar for infliximab, which came to market in March 2015 is now used by about 80% of patients receiving infliximab in the UK. Per Troein, Vice President at IQVIA, also noted how Denmark and Norway are good examples of countries that have increased their uptake of infliximab biosimilars quickly because of their use of a tender system to pay for the medicines. Justin Stebbing, Professor of Oncology at Imperial College London, questioned if biosimilar developers will still have to run the large clinical studies currently needed to prove biosimilarity, given that the sensitivity of analytical comparisons is increasing. But the lingering question for Stebbing, which he said he grapples with daily, is how to explain to cancer patients what switching them to a biosimilar version of a medicine means, or if he should even try to explain the switch since the medicines are so similar.

Gustaf Befrits, a Health Economist with the Stockholm County Council in Sweden, noted that all the patients taking infliximab in Stockholm were switched to a lower-cost biosimilar in just 2 months, and very few expressed a negative opinion of the switch, though all patients were informed of the decision. As for as predictions for the next 10 years, Troein said he expects discounts in the EU of between 25% and 70% off the original list price will be common and result in “significant volume increases.” The issues of safety, switching, and extrapolation – all of which were question marks when biosimilars first came to market in the EU 12 years ago – “will largely be gone.”

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EUROPE: UK researchers report a successful switching program to biosimilar etanercept   +

Researchers at the British Society for Rheumatology’s Annual Conference in Liverpool, UK, have presented the outcomes of a multi-disciplinary switch to biosimilar etanercept (Benepali®) from the reference product Enbrel® in patients with rheumatoid arthritis (RA) (n=151) conducted between January and June 2017. Study participants were offered an education session as well as a dedicated biosimilar switching clinic staffed by a rheumatology consultant, a registrar, and specialty pharmacist both before the switch and 4 months afterwards. The switch was predicted to result in a cost saving of approximately $675,902 (£500,000) per year. It was found that, in a relatively short period of time, a large number of patients were able to safely switch to the biosimilar in a controlled setting without loss of efficacy or increased toxicity. In total, 8 patients were switched back to the reference product (5 of whom reported subjective adverse events and 3 of whom had difficulty using the auto-injector pen). Two patients experienced disease flares. When asked how they felt about their disease control after the switch, 75% of patients said they felt no different. In addition, the method of delivery of the biosimilar was preferred by most patients, who commented on the easier technique and reduced manual dexterity required to administer the drug.

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