Submitted: 5 February 2019; Revised: 14 March 2019; Accepted: 20 March 2019; Published online first: 2 April 2019
The global market for biosimilars is valued at approximately US$4 billion, and it is growing rapidly as patents expire on an increasing number of biological drugs.
A number of important milestones were achieved during 2018 regarding approval of biosimilars.
Biosimilar approvals in 2018
Argentina’s Administración Nacional de Medicamentos, Alimentos y Tecnología Médica approved Laboratorio Elea’s ophthalmic medicamento biológico similar Lumiere (bevacizumab biosimilar) in August 2018.
In Asia, a number of biosimilars were approved and launched in 2018. Japan’s medicines regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA), approved its first darbepoetin alfa biosimilar as well as Pfizer’s infliximab biosimilar (marking Pfizer Japan’s first biosimilar approval in the country). Two South Korean firms have since announced that they have submitted applications to PMDA for approval of their proposed darbepoetin alfa biosimilars. The first etanercept biosimilar was launched in Japan in 2018 (Etanercept BS), as well as trastuzumab biosimilar 2 and agalsidase beta BS. The launch of CKD Pharma’s darbepoetin alfa biosimilar is also underway in Japan. In South Korea, the insulin glargine biosimilar Glarzia and etanercept biosimilar Eucept were approved by the Korean Ministry of Food and Drug Safety, and the trastuzumab biosimilar Samfenet and insulin glargine biosimilar Glarzia were launched. The China Food and Drug Administration (CFDA) accepted applications for approval of adalimumab copy biologicals from Hisun, Bio-Thera and Innovent. In India, a ‘similar biologic’ of adalimumab, Mabura, was launched in January 2018, and the ‘similar biologic’ of trastuzumab Hervycta was launched in July.
Australia’s drug regulator, the Therapeutic Goods Administration (TGA) approved Mylan’s insulin biosimilar Semglee, and trastuzumab biosimilars Truxima and Herzuma in 2018.
Health Canada approved Apotex’s pegfilgrastim biosimilar Lapelga in 2018. Sandoz’s etanercept biosimilar Erelzi was added to Quebec’s public drug plan in early 2018 after gaining approval from Health Canada in 2017.
The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended marketing authorization for two pegfilgrastim biosimilars, Mylan/Biocon’s Fulphila and Accord Healthcare’s Pelgraz, as well as Amgen/Allergan’s trastuzumab biosimilar Kanjinti, and Pfizer’s bevacizumab biosimilar Zirabev. EMA is reviewing Mabion’s rituximab biosimilar Mabion CD20.
The European Commission (EC) approved a number of biosimilars in 2018, including adalimumab biosimilars Halimatoz, Hefiya and Hyrimoz from Sandoz and Cyltezo from Boehringer Ingelheim. Trastuzumab biosimilars Herzuma from Celltrion, Trazimera from Pfizer and Ogrivi from Mylan/Biocon, and pegfilgrastim biosimilars Udenyca from Coherus BioSciences, Pelmeg from Cinfa Biotech and Ziextenzo from Sandoz were also approved, as well as Amgen’s bevacizumab biosimilar Mvasi and Sandoz’s infliximab biosimilar Zessly.
Biosimilars launched in Europe in 2018 include adalimumab biosimilars Amgevita from Amgen, Imraldi from Samsung Bioepis, and Hulio from Mylan/Fujifilm. Samsung Bioepis’s trastuzumab biosimilar Ontruzant and Mylan/Biocon’s insulin glargine biosimilar Semglee launched in the UK.
In 2018, the US Food and Drug Administration (FDA) approved a number of biosimilars including its first rituximab biosimilar Truxima from Celltrion, the follow-on insulin lispro Admelog from Sanofi, trastuzumab biosimilar Herzuma, and adalimumab biosimilar Hyrimoz. FDA also approved the pegfilgrastim biosimilars Fulphila and Udenyca, and two biosimilars from Pfizer – its epoetin alfa biosimilar Retacrit and its filgrastim biosimilar Nivestym.
FDA rejected a number of biosimilar applications in 2018. These include initial rejections of rituximab biosimilar Truxima and trastuzumab biosimilar Herzuma. FDA also rejected applications for trastuzumab biosimilars from Pfizer and Amgen, Sandoz’s rituximab biosimilar and Evolus’s botulinum toxin biosimilar.
FDA is reviewing Samsung Bioepis’s submission for its adalimumab biosimilar Imraldi. Taiwan-based Tanvex BioPharma submitted its first biosimilar application to FDA for its filgrastim biosimilar TX01 in October 2018.
Clinical studies for biosimilars
In 2018, results were reported from a number of clinical studies investigating the efficacy and safety profile of biosimilars including adalimumab, bevacizumab, filgrastim, infliximab, pegfilgrastim, rituximab and trastuzumab. Some of these clinical studies are summarized below.
Adalimumab is the most commonly prescribed biological. It is approved for the treatment of rheumatoid arthritis (RA). as well as psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis. Results from the VOLTAIRE-RA equivalence phase III trial, which compared outcomes in patients with active RA randomized to Boehringer’s adalimumab biosimilar Cyltezo or AbbVie’s reference product Humira, and patients switched from Humira to Cyltezo, were published in 2018. The results indicate that efficacy outcomes and the safety and immunogenicity profiles were similar between the groups. In September, Boehringer announced positive phase III data for Cyltezo as a treatment for moderate-to-severe chronic plaque psoriasis. The results, according to Boehringer ‘confirm that Cyltezo is equivalent to Humira, with no clinically meaningful differences in efficacy, safety and immunogenicity in people with moderate-to-severe chronic plaque psoriasis’.
A phase III trial compared the efficacy and safety profile of Sandoz’s adalimumab biosimilar, Hyrimoz (GP2017) with reference adalimumab in patients with moderate-to-severe RA with inadequate response to disease modifying anti-rheumatic drugs. The results from the study demonstrate, according to the authors, that Hyrimoz is of equivalent efficacy to the reference adalimumab in this patient group and that the ‘safety and immunogenicity of GP2017 and reference adalimumab were similar and consistent with clinical experience with reference adalimumab’.
Samsung Bioepis and Biogen conducted an analysis combining data from three phase III trials that compared the efficacy and safety of anti-tumour necrosis factor (TNF) biosimilars to their reference biologicals. The pooled analysis included data from Benepali (etanercept biosimilar), Flixabi (infliximab biosimilar) and Imraldi (adalimumab biosimilar) and assessed the impact of anti-drug antibodies (ADAs) on efficacy and tolerability, as well as radiographic progression by disease activity state. Immunogenicity data from 1,710 patients with moderate-to-severe RA revealed that the incidence of ADAs was comparable between the biosimilars and their reference products, and that the development of ADAs is associated with reduced clinical efficacy and increased incidence of injection site reactions/infusion-related reactions in patients with RA.
Researchers from mAbxience presented data from a phase I trial supporting the pharmacokinetic (PK) bioequivalence of their bevacizumab biosimilar BEVZ92 with originator bevacizumab Avastin as a first-line treatment in patients with metastatic colorectal cancer.
A phase III clinical trial comparing Pfizer’s candidate bevacizumab biosimilar PF 06439535 with originator bevacizumab in patients with advanced non-squamous non-small cell lung cancer found that PF 06439535 and reference bevacizumab had similar objective response rates, progression-free survival, overall survival, and safety and immunogenicity profiles.
In January 2018, Japan-based collaborators Kissei and JCR announced positive results from the phase III trial of their candidate darbepoetin alfa biosimilar, JR 131 in renal anaemia patients with chronic kidney disease. The results showed that ‘JR 131 demonstrated equivalence in efficacy and safety compared with darbepoetin’, according to the companies.
Researchers in Italy carried out a prospective cohort study to compare the safety profiles of biosimilars with respect to their reference products in a nephrology setting. The results confirm the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis.
Results from YL Biologics’s global phase III trial showed that its etanercept biosimilar YLB113 had similar efficacy and a similar safety profile to the reference Enbrel in Japanese patients with RA.
Researchers from Germany compared results from the phase III PIONEER trial of Sandoz’s biosimilar filgrastim (Zarxio) with post-approval data from the MONITOR-GCSF study, concluding that Zarxio ‘prevented febrile neutropenia in a randomized controlled trial and in real-world practice in breast cancer patients receiving (neo-)adjuvant chemotherapy’.
The efficacy and safety profile of Amgen’s infliximab biosimilar ABP 710 was compared with the originator biological infliximab, Johnson & Johnson/Merck’s Remicade, in patients with moderate-to-severe RA in a phase III clinical trial. According to Amgen, the results confirm that ABP 710 was non-inferior to Remicade but could not rule out superiority based on the primary endpoint which measured response by a 20% or greater improvement defined by the American College of Rheumatology Criteria. Amgen believes that the totality of the evidence generated ‘supports ABP 710 as highly similar to the reference product’. Overall, the safety and immunogenicity profiles of ABP 710 and Remicade were comparable.
In June 2018, Sandoz announced positive results from its phase III REFLECTIONS B537 02 trial for its infliximab biosimilar Zessly in patients with moderate-to-severe active RA. The results showed, according to Sandoz, that Zessly was comparable to the reference infliximab Remicade in terms of safety profile, efficacy and quality.
Celltrion is developing a subcutaneous version of its infliximab biosimilar Remsima (CT-P13). In June 2018, Celltrion announced that data from its phase I study showed that the subcutaneous administration of Remsima was comparable with intravenous administration of Remsima/Inflectra in terms of efficacy outcomes and safety profile in patients with active Crohn’s disease. In August, Celltrion announced the completion of a phase III trial with subcutaneous Remsima.
Authors of a systematic review assessing the similarity of biosimilar insulins to their reference products concluded that the studies identified ‘suggest similar clinical efficacy and safety’ compared with their reference products. They added that ‘these biosimilars may be considered as alternative options for non-basal and basal insulin therapy in patients with type 1 and type 2 diabetes’.
Indian generics maker Glenmark announced in July 2018 that results from a phase I study suggest similarity in PK, PD and safety and immunogenicity profiles between its proposed omalizumab biosimilar GBR 310 and the originator product Xolair.
Canada-based Apobiologix reported results of an international phase III trial investigating biosimilarity between its proposed pegfilgrastim biosimilar Lapelga and Amgen’s US-licensed and EU-approved reference product Neulasta in early stage breast cancer patients. The results demonstrated that the biosimilar was highly similar to Neulasta with regard to the efficacy and safety endpoints investigated in the study.
In a phase III clinical trial in patients with low tumour burden follicular lymphoma (FL), Celltrion’s rituximab biosimilar CT-P10 and the originator rituximab, Roche’s MabThera/Rituxan demonstrated equivalent efficacy and PKs. Celltrion also recently presented positive phase III results for CT-P10 in patients with advanced FL, reporting that the efficacy outcomes and safety profile of CT-P10 was comparable to originator rituximab.
The efficacy and safety profile of Shanghai Henlius Biotech’s rituximab copy biological HLX01 in previously untreated patients with CD20+ diffuse large B-cell lymphoma was investigated in a phase III trial. The authors concluded that the results ‘successfully demonstrate equivalence in PK and pharmacodynamics (PDs), efficacy and safety between HLX01 and originator rituximab sourced from China’.
Pfizer’s proposed rituximab biosimilar PF 05280586 was compared with originator rituximab in a phase III trial in patients with CD20+, low tumour burden FL. The results of the study demonstrated, according to the authors, that the ‘efficacy, safety and immunogenicity, PK and PD of PF 05280586 and rituximab-EU were similar’.
A multinational phase III trial comparing PK and PD of mAbxience’s proposed biosimilar RTXM83 with originator rituximab in patients with diffuse large B-cell lymphoma supported the claim of biosimilarity.
Studies assessing rituximab biosimilars tend to be large and expensive clinical trials assessing PK and PD. Researchers from Austria and Canada piloted a different approach using the half-maximal effective dose (ED50) in healthy volunteers to investigate the effects of a proposed biosimilar rituximab with the originator product. The authors concluded that their trial demonstrates an alternative, cost-effective, more sensitive approach to comparing PD of biosimilars of rituximab using pharmacological principals.
Celltrion presented phase III clinical trial data supporting the PK similarity of its trastuzumab biosimilar CT-P6 to the originator trastuzumab (Roche’s Herceptin) in patients with human epidermal growth factor receptor positive (HER2+) early-stage breast cancer.
In early 2017, Mylan and Biocon reported that the results from their phase III HERiTAge study ‘confirm the efficacy, safety and immunogenicity of Ogivri, in comparison to branded trastuzumab’. In 2018, the authors reported the results of the secondary endpoints of safety and immunogenicity, concluding that ‘maintenance monotherapy with FDA-approved trastuzumab-dkst [Ogivri] after combination with taxane was well tolerated, with safety and efficacy profiles similar to originator trastuzumab’.
Results from a clinical trial assessing Samsung Bioepis’s trastuzumab biosimilar Ontruzant in patients with HER2+ early-stage breast cancer ‘demonstrate the long-term safety profile’ of Ontruzant, according to the authors.
A multinational phase III trial investigated the efficacy, safety and immunogenicity profile of Shanghai Henlius Biotech’s trastuzumab copy biological HLX02 and originator trastuzumab in HER2+, locally recurrent or previously untreated metastatic breast cancer patients. The results showed, according to the authors, that the ‘three-way PK and safety equivalence of HLX02 and reference trastuzumab were demonstrated’.
Regulation and guidance on biosimilars
The EC announced a proposal to refine the intellectual property rules in Europe in May 2018. This included an ‘export manufacturing waiver’ to Supplementary Protection Certificates (SPCs; which extend the protection of a product protected by an underlying patent also held by the applicant). The waiver allows EU-based companies to manufacture a generic or biosimilar version of an SPC-protected medicine during the term of the certificate, if done exclusively for the purpose of exporting to a non-EU market where protection has expired or never existed. The EC claims the waiver ‘will support Europe’s pioneering role in pharmaceutical research and development,’ however, some industry groups expressed concerns. The European Federation of the Pharmaceutical Industries and Associations (EFPIA) stated that the waiver ‘jeopardises patient access to innovative treatments’ while the European Biopharmaceutical Enterprises said that it ‘reduces intellectual property rights and de-values the incentives framework’.
In July 2018, the Australian TGA made an amendment to its biological’s regulation. Under the new regulation, a substance will be regulated as a biological rather than a blood component if it is subject to processing involving ‘more than minimal manipulation’. This broader definition incorporates conditioned serum and adipose-derived cell extracts, which had previously been excluded from regulation. This regulation is similar to EMA’s approach for stem cell products and also mimics similar regulations in the US. As of September 2018, manufacturers are no longer able to request parallel processing when submitting a biosimilar application for approval until after the TGA has made a determination of biosimilarity.
In August 2018, the US announced a new ‘understanding’ on trade with Mexico as part of efforts to re-negotiate the North American Free Trade Agreement between Canada, Mexico and the US. This includes providing 10 years of exclusivity for biologicals which could potentially hinder competition and access to biosimilars.
As part of plans to provide additional clarification on its 2009 guidelines on the evaluation of biosimilars, the World Health Organization (WHO) drafted a document in 2018 providing answers to questions that regulators have posed over the past eight years.
In June 2018, FDA published guidance providing recommendations to industry on formal meetings between FDA and sponsors or applicants relating to the development and review of biosimilars or interchangeable biological products. It also issued final guidance on the Biosimilar User Fee Act (BsUFA) II fee structure, finalizing the changes introduced since BsUFA I. Also, in June, FDA announced that it had withdrawn its draft guidance on analytical studies of biosimilars following public comments. In July, FDA issued two new guidance documents providing recommendations to industry on labelling requirements for prescription drugs and biologicals. In December 2018, the agency released four guidance documents and a proposed rule on the definition of a ‘biological product’. This guidance provides greater clarity on scientific and regulatory considerations for the development of biosimilar and interchangeable products, and describes how it plans to transition certain biological products approved as drugs to be licensed as biologicals. FDA also clarified that products reclassified as biologicals will not receive the 12-year exclusivity period afforded to newly licensed biologicals.
A proposed amendment to the Hatch-Waxman Act was filed in June 2018 by Senator Hatch, aiming to restore the careful balance the Hatch-Waxman Act struck to incentivize generics development. The amendment requires that a generic drug applicant must not use an inter partes review or post-grant review for a patent covering the innovator drug if it plans to use the abbreviated Hatch-Waxman pathway to approval.
South Korea’s financial authority released new ‘relaxed’ guidelines for how drug companies should list research and development ‘R & D’ spending as assets in September 2018. The guidelines say that drug companies can capitalize their research spending after regulatory approval of phase III trials, and biosimilar makers can capitalize their research spending from the phase I stage.
In March 2018, the Spanish Society of Gastroenterology (Sociedad Española de Patología Digestiva) updated its position statement in support of the development and use of biosimilars for the treatment of inflammatory bowel disease (IBD). This reflects the growing body of evidence supporting the biosimilarity of Remsima/Inflectra (CT-P13) with originator infliximab as a treatment for IBD. It follows the 2017 update to the European Crohn’s and Colitis Organisation position statement which supports switching from originator Remicade to biosimilar infliximab in IBD patients.
In March 2018, the American Society of Clinical Oncology (ASCO) issued a position statement on biosimilars in oncology. The statement reflects the society’s views on issues such as naming, labelling, safety and efficacy, interchangeability, switching and substitution, and prescriber and patient education. In May, the Brazilian Society of Clinical Oncology issued a position statement on ‘follow-on biological products’ in oncology addressing similar issues to those ASCO addressed, as well as the potential impact that ‘follow-on biological products’ may have on the financial burden in healthcare.
The Association of British Clinical Diabetologists issued a position statement on the use of biosimilar insulin in December 2018. The statement summarises information on the advantages and disadvantages of using biosimilar insulins and gives the association’s position on when biosimilar insulins should be used.
Naming of biologicals remained a contentious issue during 2018. WHO first proposed the concept of a biological qualifier (a four-letter alphabetic code for all biologicals) in 2014. In December 2018, authors from the US urged WHO to finalise its guidance, stating that ‘precise naming will improve patient safety by reducing confusion and mishaps in prescribing and dispensing’ .
The FDA’s finalized guidance on naming biologicals assigns a non-proprietary or ‘proper’ name to all originator biologicals, related biologicals and biosimilars. The proper name applies prospectively and retrospectively and consists of a combination of the ‘core name’ and a meaningless suffix composed of four lowercase letters. Concerns have been raised that this naming convention creates the impression that the clinical effects of a biosimilar may differ meaningfully from the reference product. Groups such as the International Generic and Biosimilar Medicines Association, have called for biosimilars to share the proper name with the reference biological.
Following an open consultation on how to name biologicals, Australia’s TGA concluded in February 2018 that ‘implementation will involve making the product’s trade name, as well as the non-proprietary name, a mandatory field when reporting an adverse event to the TGA in order to provide product specificity’.
Interchangeability and substitution
According to FDA, ‘an interchangeable biological product, in addition to meeting the biosimilarity standard, is expected to produce the same clinical result as the reference product in any given patient, and for a product that is given to a patient more than once, the risk in terms of safety and effectiveness of alternating or switching between the interchangeable and the reference product is not greater than the risk of using the reference product without alternating or switching’. Interchangeability is important because without it, payers are unlikely to encourage switching from an originator product to a biosimilar, even if they pursue formulary policies which favour biosimilars for new start patients.
A review published in early 2018 reported that the slow development of clear US guidance on interchangeability is limiting price competition. At the FDA biosimilars meeting in September 2018, there was a call to include interchangeability information in the ‘Purple Book’.
The debate over substitution practices continues. Pfizer conducted an internal global survey of 82 countries in which it examined biosimilar pharmacy-mediated substitution in 2017 and found that no universal position is held worldwide on substitution of biosimilars [2, 3].
According to the US Biologics Price Competition and Innovation Act of 2009 (BPCI Act), only a biological that has been approved as interchangeable may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. Many US states are considering, or have introduced, laws related to the substitution of biosimilars at the pharmacy level. In February and March 2018, bills in Michigan, South Dakota and West Virginia were passed to authorize pharmacists to substitute a biosimilar for a prescribed biological product if the biosimilar has been approved by FDA as ‘therapeutically equivalent’ and the prescriber has not indicated ‘d.a.w.’ (dispense as written) on the prescription.
Switching is defined as a decision by the treating physician to exchange one medicine for another medicine with the same therapeutic intent in patients who are undergoing treatment. This can involve switching between a reference product and a biosimilar, or between biosimilars. Attitudes to switching continue to change.
The European Specialist Nurses Organisations launched a guide for switching from reference biologicals to biosimilars in June 2018. The guide is specifically directed towards specialized nurses and aims to provide information to facilitate interactions with patients switching from a reference biological to a biosimilar (or vice versa), or between biosimilars of the same reference product.
Some of the trials investigating switching to biosimilars which were published in 2018 are summarized below.
Results from the VOLTAIRE-RA equivalence phase III trial in patients with active RA showed that a switch from reference adalimumab Humira to biosimilar Cyltezo had no significant impact on efficacy outcomes. Safety and tolerability profiles were similar in the group continuing treatment with Humira and the group switched to Cyltezo.
Results from a UK study suggest that switching from originator etanercept Enbrel to biosimilar Benepali is safe and effective in a hospital setting for patients with RA, ankylosing spondylitis and psoriatic arthritis.
Results from the phase III EQUIRA study suggest that there is no impact on efficacy, safety or immunogenicity outcomes when patients with moderate-to-severe RA are switched from reference etanercept to Sandoz’s etanercept biosimilar, Erelzi.
Following the landmark NOR-SWITCH clinical trial which failed to find inferiority when switching from originator infliximab Remicade to biosimilar Remsima/Inflectra, a number of studies have investigated the switch from Remicade to other biosimilars.
The phase III REFLECTIONS B537–02 trial evaluated the effects of switching from Remicade to the biosimilar Zessly in patients with moderate-to-severe active RA. The research indicated that patients who switched from Remicade to Zessly had similar efficacy outcomes and a similar safety and immunogenicity profile to patients who continued to use Remicade.
French researchers assessed the long-term retention rate of Remsima/Inflectra after switching from Remicade. They compared this with the retention rate observed in a historic cohort of patients treated with Remicade from a previous study carried out by their group. According to the authors, the results suggest that a nocebo effect occurred in the first weeks after the switch which initially lowered the biosimilar retention rate. After this initial nocebo effect, originator and biosimilar retention rates appeared to be identical, supporting the safety, efficacy and acceptability of the switch in the long term. The authors conclude that ‘initial information provided before the switch appears to be crucial for biosimilar acceptance and therefore reducing the nocebo effect’.
Results from a retrospective cohort study conducted by Italian and Spanish researchers on the immunogenicity of Remsima/Inflectra suggest that there is full interchangeability between infliximab biosimilars with respect to immunogenicity profiles.
Researchers carried out a retrospective chart review using the electronic medical records of patients hospitalized at a Chinese hospital from 2005 to 2016. They found that switching from copy insulin glargine biological Basalin to originator Lantus is effective in patients with diabetes. However, in light of another recently published study that had contrasting findings, the authors recommend that further studies be carried out.
Cost savings associated with biosimilar use
Use of biosimilars can result in significant savings to health systems.
US-based biosimilars specialist Coherus announced in November 2018 that it would price its pegfilgrastim biosimilar at a 33% discount to the originator product, Amgen’s Neulasta. Also, in November, it was reported that Pfizer launched its epoetin alfa biosimilar, Retacrit, in the US at a significant discount. According to reports, Pfizer began shipping Retacrit to wholesalers at a 57% discount compared with Amgen’s Procrit and a 33.5% discount compared with Johnson & Johnson’s Epogen.
A study assessing the use and costs of targeted therapies for cancer treatment in Southern Italy from 2010 to 2014 estimated that, assuming an uptake of biosimilar trastuzumab and rituximab of 50%, almost Euros 1 million could be saved annually.
Researchers from Canada compared the cost-effectiveness of infliximab biosimilar Inflectra to originator Remicade for the management of Crohn’s disease. Using a Markov model with a 5-year time horizon and a willingness-to-pay threshold of CA$50,000 per quality-adjusted life year, they found that Inflectra has an 83% probability of being cost-effective while Remicade has a 17% probability of being cost-effective.
In February 2018, Canadian not-for-profit healthcare benefits specialist, Green Shield Canada, announced that it was ‘the first major benefits carrier to preferentially list biosimilars’. In September 2018, New Zealand’s Pharmac announced that it will stop funding Janssen’s brand-name epoetin alfa biological Eprex and will only fund the biosimilar epoetin alfa Binocrit supplied by Novartis.
Barriers to uptake of biosimilars
The outlook for biosimilars looks promising. There are an increasing number of global biosimilar approvals based on positive efficacy and safety data, and cost analyses are generally finding that biosimilars have the potential to provide significant savings for healthcare systems globally. A number of countries have implemented strategies to stimulate the biosimilars market. In July 2018, FDA released its Biosimilars Action Plan, which aims to improve the efficiency of the biosimilar and interchangeable product development and approval process. France is strongly in favour of biosimilars and aims to reach 80% biosimilar penetration by 2022 as part of its 2018–2022 National Health Strategy, representing an increase from the previous year’s 70% target. This follows a revamp of the substitution policy in 2017 and the creation of a biosimilar registry. Meanwhile, Ireland has updated its National Biosimilars Medicine Policy in a bid to increase biosimilar use in the country.
However, barriers to the uptake of biosimilars still exist.
One of the main barriers is the perception that biosimilars may not have been studied thoroughly enough and therefore that they may not be safe. This perception, according to a recent review, comes from a lack of knowledge about the scientific principles underlying the development and licensing of biosimilars, and the inappropriate labelling of non-originator and copy-version products as biosimilars. The authors recommend that regulatory authorities develop a specific regulatory framework for approving biosimilars that is distinct from the regulatory procedures previously applied to copy-version products. Communication and education of patients is also important, and the review recommends the publication of public assessment reports on biosimilars as a way to increase transparency and public trust in biosimilars. The Biosimilar Working Group of the International Pharmaceutical Regulators Forum published a template for biosimilar assessment reports that could be used by regulators worldwide, entitled Public Assessment Summary Information for Biosimilars.
In a move to increase confidence in biosimilars, EMA and the EC published new material in September 2018 including an animated video for patients that explains key facts on biosimilars and how EMA works to ensure that biosimilars are as safe and effective as their reference biologicals. EMA also published translations of its biosimilar guide for healthcare professionals in Dutch, French, German, Italian, Polish, Portuguese and Spanish.
A recent study found that only 3% of US spending on biologicals is subject to competition from biosimilars. There are therefore huge potential savings to be made with increased use of biosimilars. The study reported that current obstacles to the development and uptake of biosimilars in the US include uncertainty over naming, the slow development of clear guidance on interchangeability, and secrecy about manufacturing processes. In addition, the author believes that consolidation of a reference product and all its biosimilars under a single billing code ‘would probably generate strong price competition’.
Prescribing incentives can be used to increase the uptake of biosimilars. In September 2018, the Australian Pharmaceutical Benefits Scheme announced the implementation of two specific drivers to encourage the use of biosimilars, which it says will complement the Biosimilar Awareness Initiative. These drivers are: 1) encouraging prescribing of a biosimilar brand rather than the reference biological brand for treatment naïve patients; and 2) providing a simpler and faster approval process for prescribing biosimilar brands (streamlined authority), while maintaining an existing higher-level authority requirement for the reference biological brand (written authority). Further, the TGA announced that it will require mandatory reporting of drug shortages from sponsors of medicines in Australia, starting from 1 January 2019.
Knowledge sharing is also an important factor for promoting use of biosimilars. The Spanish Association of Biosimilar Medicines and the Federation of Spanish Medical Scientific Associations signed a collaboration agreement in March 2018 that includes the creation of a joint working group to share up-to-date information on biosimilars. The agreement aims to generate and disseminate knowledge about biosimilars for medical professionals.
Collaborations, agreements, and investment in biosimilars
Many collaborations were formed in 2018, and a number of important investments in biosimilars were made.
In January 2018, Biocon and Sandoz announced a global partnership to develop, manufacture and commercialize new next-generation biosimilars.
Fujifilm Kyowa Kirin Biologics announced in April 2018 that it will partner with Mylan to commercialize its adalimumab biosimilar Hulio. Mylan will be granted exclusive commercialization rights for Hulio in Europe.
US-based biotech Pfenex and China’s NT Pharma announced an agreement in April 2018 concerning PF708, a candidate biosimilar of Eli Lilly’s osteoporosis treatment Forteo (teriparatide). Pfenex granted NT Pharma non-exclusive development and exclusive commercialization rights to PF708 in mainland China, Hong Kong, Singapore, Malaysia and Thailand.
US generics maker Amneal and biosimilar specialist mAbxience announced in May 2018 that they have signed an exclusive licensing and supply agreement in the US for mAbxience’s candidate bevacizumab biosimilar.
India-based Lupin announced in June 2018 that Mylan will commercialize its proposed etanercept biosimilar in a number of markets.
In July 2018, German generics giant Stada and Swedish biotech company Xbrane announced that they had entered into a co-development agreement for Xlucane, a proposed ranibizumab biosimilar.
In September 2018, Iceland-based biopharmaceutical company Alvotech announced that it was entering into a joint venture with China-based Changchun High & New Technology Industries Group, which will enable Alvotech to develop, manufacture and commercialize its biosimilar portfolio in China.
In November 2018, Alvotech and Japan-based Fuji Pharma announced they had entered into a partnership whereby Alvotech will develop and supply biosimilars from its current pipeline and Fuji Pharma will then be responsible for registering and selling the biosimilars in Japan.
AbbVie signed yet more deals regarding biosimilar versions of Humira (adalimumab) in 2018. In July, AbbVie announced patent license agreements with Mylan which will allow Mylan to launch its biosimilar adalimumab in the US in 2023. In October, AbbVie announced global resolution of patent disputes with Sandoz and Fresenius Kabi and in November, it announced agreements with Momenta and Pfizer. These agreements will allow Fresenius Kabi and Sandoz’s adalimumab biosimilars to be launched in the US in September 2023, and Momenta and Pfizer’s biosimilars to be launched in the US in November 2023. Samsung Bioepis reached a settlement with AbbVie in April 2018 under which it could launch its biosimilar Imraldi in the EU in October 2018, and in the US in June 2023. Imraldi has been making waves in Europe, gaining more than 60% of the adalimumab market in Germany as of early 2019. The only company still resisting a deal with AbbVie is Boehringer.
The Orion Group announced in October 2018 that it will distribute Amgen’s adalimumab biosimilar Amgevita in Finland.
According to a study into how the landscape of biosimilars development is changing, manufacturing is moving to Asia, with biosimilars developed in Korea contributing 43% of the global biosimilars value, up from 0% in 2012. Indian generics maker Cadila and Indonesia-based Kalbe are both making advances into the biosimilars field. In February 2018, Cadila announced that it was carrying out a phase I clinical trial for its pegfilgrastim similar biologic, and Kalbe inaugurated its factory in Cikarang, West Java, which will produce biotechnology-based medicines. In March 2018, Lupin announced that it had entered into an agreement with the Council of Scientific and Industrial Research-National Chemical Laboratory and the Department of Science and Technology to conduct research on a continuous purification process development of a ‘similar biologic’ monoclonal antibody. In April 2018, China-based WuXi Biologics, announced that it is expanding its biologicals manufacturing capacity with new facilities planned in China, Ireland, Singapore and the US. Biocon has stated that its biosimilars plant in Bangalore has received a clean bill of health, indicating that it is now compliant with FDA manufacturing requirements. Samsung BioLogics announced in July 2018 that it had been licensed by FDA to manufacture a monoclonal antibody drug product at its first plant.
Discontinuation of biosimilars
The development of some biosimilars was abandoned in 2018.
In October 2018, Merck pulled out of a deal with Samsung Bioepis, terminating the development and commercialization agreement between the two companies for insulin glargine biosimilar Lusduna. Merck has faced significant challenges in bringing Lusduna to the market in the US, including patent litigation from originator manufacturer Sanofi.
German generics giant Stada Arzneimittel announced in March 2018 that it would halt development of its adalimumab biosimilar as part of a move to focus its speciality pharmaceuticals on oncology, central nervous system, diabetes and ophthalmology. US-based biotechnology firm Momenta announced in October 2018 that it would be focusing on two key biosimilars and halt the development of five others. In November 2018, Sandoz announced that it would no longer pursue approval for its rituximab biosimilar (GP2013) in the US ‘at this time’. Boehringer has said that it will not commercialize its approved adalimumab biosimilar Cyltezo in Europe and is discontinuing all biosimilar development activities outside the US.
Summary and recommendation
Key considerations for increasing biosimilar market penetration include increasing harmonization around the world with regard to regulatory approval guidance, and approach to interchangeability and switching practices. Reaching consensus on naming of biologicals and biosimilars is a key factor in ensuring safe dispensing and tracking.
Government policies need to be introduced to support increased uptake of biosimilars, for example, prescribing incentives for healthcare professionals. Patient confidence in biosimilars is key to acceptance, therefore interventions aimed at improving patient education on the efficacy and safety of biosimilars are likely to increase market adoption.
A 2018 review has suggested a number of recommendations to FDA to encourage the faster development and adoption of biosimilars in the US, which were the subject of a citizen petition filed to FDA. These include waiver bridging studies (currently required where there is a non-US product as a reference product), encouraging substitution for naïve patients, allowing in vivo immunogenicity study waivers, making PK profiling clinically relevant, modifying tier testing criteria for analytical similarity, clarifying analytical testing validation, encouraging development of novel testing methods, accepting smaller batch sizes and minimizing clinical studies .
It should be noted that ‘copy biologicals’ approved in China, ‘similar biologics’ approved in India, and ‘similar biotherapeutic products’ approved in Latin America might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The EMA (European Medicines Agency) regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product.
Competing interests: None.
Provenance and peer review: Article prepared with data from GaBI Online and GaBI Journal; internally peer reviewed.
Sophie Shina, MSc, GaBI Journal Editor
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