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A new systematic literature review conducted by authors in Eastern Europe and the Netherlands has concluded that concerns about switching clinically stable patients from an originator to a biosimilar are “overhyped.” Fifty-eight papers (12 empirical papers, 5 systematic reviews, and 41 non-empirical papers) were included in the review, which found that “preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access.”
In an important and decisive victory for the US biosimilars industry, the US Supreme Court has overturned an earlier ruling by a Federal Appeals Court that had mandated the need for biosimilar makers to provide originator manufacturers with 180 days’ notice of their intention to launch after gaining US Food and Drug Administration (FDA) approval. In their unanimous verdict, the Supreme Court justices ruled that the notice period could begin prior to FDA approval. Sandoz and Amgen, the two parties involved in the case, had been battling since 2014 over conflicting interpretations of the Biologics Price Competition and Innovation Act (BPCIA), which established an expedited path for regulatory approval of biosimilars.
According to the Supreme Court’s ruling, Sandoz’s notice, given in 2014 while their application for approval of Zarxio® (a biosimilar of filgrastim) was pending with the FDA, satisfied the BPCIA’s requirement. “In sum, because Sandoz fully complied with [the BPCIA] when it first gave notice (before licensure) in July 2014, the Federal Circuit erred in issuing a federal injunction prohibiting Sandoz from marketing Zarxio® until 180 days after licensure,” Justice Clarence Thomas wrote. He added that the ruling was based on the wording of the BPCIA, which he said does not impose the timing requirements that the Federal Circuit did in granting its injunction. “Even if we were persuaded that Amgen had the better of the policy arguments, those arguments could not overcome the statute’s plain language, which is our ‘primary guide’ to Congress’ preferred policy,” Thomas wrote. The ruling was applauded not only by Sandoz but by many other biosimilar developers and advocates who view it as a significant milestone for the US biosimilars industry.
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) to Coherus BioSciences, rejecting its application for CHS-1701, a candidate biosimilar of pegfilgrastim (Amgen’s Neulasta®), which Coherus has referred to as the highest selling oncology biologic in the US. The FDA has not requested a clinical study of CHS-1701 in oncology patients (as anticipated by some), but its CRL asks Coherus to reanalyse a subset of samples with a revised immunogenicity assay and to provide additional manufacturing-related information. News of this setback comes just 5 months after Sandoz withdrew its pegfilgrastim product from European Medicines Agency (EMA) consideration after being issued a list of questions, and also having received its own CRL from the FDA. Coherus has said that it will work with the FDA to address the outstanding concerns but, in the coming months, all industry eyes are likely to be on Mylan and Biocon’s attempt at a pegfilgrastim biosimilar, MYL-1401H.
Meanwhile, the FDA has also issued a CRL to Pfizer, rejecting its biosimilar of Amgen’s epoetin alfa (Epogen®) for the second time. Just a month previously, an FDA advisory committee had strongly recommended Pfizer’s epoetin alfa biosimilar for approval by a vote of 14–1. The reason for the CRL – which came as a surprise to many – related purely to Pfizer’s proposal to manufacture the product at a facility in McPherson, Kansas, USA, which had been criticised by the FDA on previous occasions for falling short of quality standards.
According to a new report from healthcare consultancy Avalere Health, biosimilars are steadily gaining acceptance by the US health insurance industry. A survey of 45 health plans shows 81% are covering at least one biosimilar product, in the interests of achieving cost savings without comprising efficacy or safety. Ironically, however, a new study announced by another healthcare consultancy, Navigant, has shown that use of biosimilar drugs leads to a reduction in savings for most providers. Although biosimilars have the potential to reduce treatment costs, the savings are not realized for most providers mainly due to the “buy-and-bill” reimbursement model for infused therapies. The Centers for Medicare & Medicaid Services (CMS) incentivizes the use of biosimilars through reimbursement, but private payers generally don't, the Navigant study said. Because the reimbursement under CMS is more favorable, biosimilars become more attractive as the percentage of Medicare patients increases – but the fact that over 50% of a provider’s business needs to come from Medicare to make a biosimilar an economical choice means the situation is unrealistic.
A recent viewpoint column published online in JAMA Oncology, lists other barriers to US cost savings from biosimilars, including: the modest discounts for biosimilars launched so far in the US; a 12-year period of market exclusivity for originator biologics; a patent resolution process under the Biologics Price Competition and Innovation Act (BPCIA) that has resulted in numerous lawsuits; and the lengthy delays in finalizing the FDA’s guidance on biosimilar interchangeability.
The European Medicines Agency (EMA) has approved two new biosimilars from Sandoz: Rixathon®, a biosimilar of rituximab, and Erelzi®, a biosimilar of etanercept. Rixathon® – the second rituximab biosimilar approved by the EMA after Celltrion’s Truxima™ a few months previously – was approved for use in all licensed indications of the originator (Roche’s MabThera®), including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. Erelzi® – the second etanercept biosimilar approved by the EMA after Biogen’s Benepali® – was also approved for all licensed indications of its originator (Amgen’s Enbrel®) including rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and juvenile idiopathic arthritis.
A real-world study of patients in Sweden (n=2938) who were switched from originator etanercept (Enbrel®) to a biosimilar (Biogen’s Benepali®) has found that 11% switched back after a median of 55 days. However, Lara Lucchese, Senior Consultant at QuintilesIMS in London, UK, who was one of the study investigators, stated that the data must be interpreted with caution because the reasons for switching back were unknown, and might be explained by patient/physician beliefs and expectations, principally the “nocebo” effect. Following its approval in April 2016, the number of prescriptions for Benepali® increased steadily, accounting for 50% of the Swedish etanercept market in less than a year, even though the use of biosimilars is not compulsory in Sweden. The study investigators speculated that the speed of uptake may have left little time for appropriate patient communication and education. “If I switch a patient to a biosimilar drug, and tell them that I’m sorry but I have to provide the cheaper drug now because the GDP is so low in our country, then you have the so-called nocebo effect. You have already introduced a negative impact on the efficacy of the treatment.” they observed.
Biogen has been quick to reveal its own real-world data, which showed that – in 1548 patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who were switched from Enbrel® to Benepali® – disease activity at 3 months post-switch was comparable with that observed in the 3 months prior to the switch. In presentations at this year’s Annual European Congress of Rheumatology (EULAR), Biogen also shared data from the UK and the Netherlands highlighting patient acceptance of Benepali and adherence to treatment among those who were switched from reference etanercept according to a defined transition protocol.
Danish researchers have revealed that a government-mandated switch from originator infliximab (Remicade®) to the biosimilar CT-P13 (which was 64% cheaper) over a period of only 2 months, did not – as feared – lead to a heightened demand for healthcare support. There was concern at the time that patient and physician anxiety about biosimilars – and the rapidity of the switch period – would result in an increase in healthcare resource utilization, which could offset the cost savings. However, it turned out in the end that there was no significant escalation in use of healthcare resources.
Nonetheless, to address the doubts and unease expressed by patients who were interviewed about the switch, the Danish Rheumatism Association participated in a national program, the details of which were presented at this year’s Annual European Congress of Rheumatology (EULAR) in Madrid. Implemented throughout 2016, the program focused on monitoring the efficacy and safety of biologics and biosimilars at a batch level, as well as a national level, and the provision of more comprehensive, independent patient information. In addition, regional hospitals have invited a representative from the Danish Rheumatism Association to participate in a working group, which aims to include the patient perspective in future national recommendations on the use of biologics and biosimilars.
The independent Pharmaceutical Benefits Advisory Committee (PBAC) – which makes recommendations to the Australian Government on what medicines should be subsidised for consumers – has issued a public statement intended to offer reassurance about the safety of biosimilars in the wake of its controversial “A” flagging policy. This policy designates approved biosimilars as interchangeable with their originators and hence substitutable by pharmacists. In its statement, the PBAC said it was concerned about the possible spread of misinformation regarding biosimilar safety and the details of its policies. The statement included a link to information providing scientific justification for A flagging, and went on to say that switching to biosimilars is nonetheless not mandatory and that physicians may still choose to prescribe by brand name to avoid biosimilar substitution (or to tick a box on the prescription forbidding substitution). The PBAC also stressed that patients also continue to have the ultimate say regarding which product they receive.