Submitted: 30 January 2018; Revised: 8 February 2018; Accepted: 12 February 2018; Published online first: 26 February 2018

The past year has once again been a busy one for the biosimilars industry. Important milestones achieved during 2017 were the biosimilar approvals of Renflexis (infliximab-abda), Cyltezo (adalimumab-adbm), Mvasi (bevacizumab-awwb), Ixifi (infliximab-qbtx) and Ogivri (trastuzumab-dkst), along with the approval of follow-on insulin lispro biological Admelog, by the US Food and Drug Administration (FDA).

The agency is also reviewing applications for Amgen/Allergan’s proposed trastuzumab biosimilar (ABP 980), Sandoz’s rituximab biosimilar (GP2013) and Adello’s filgrastim biosimilar, as well as trastuzumab (CT-P6) and rituximab (CT-P10) biosimilars from Celltrion. The agency, however, delayed approval of Biocon/Mylan’s proposed pegfilgrastim biosimilar MYL-1401H. The complete response letter (CRL) relates to the update of the biosimilar application with chemistry, manufacturing and control (CMC) data after Biocon made plant modifications requiring ‘requalification’ at its Bangalore facility.

FDA’s Oncologic Drugs Advisory Committee (ODAC) also recommended that epoetin alfa biosimilar Epoetin Hospira be approved in May 2017. However, the biosimilar was rejected less than a month later after a CRL cited manufacturing issues at Hospira’s facility in McPherson, Kansas, USA. The agency also rejected Coherus BioSciences (Coherus) candidate pegfilgrastim biosimilar, CHS-1701, saying that it wanted a ‘re-analysis of a subset of subject samples with a revised immunogenicity assay’ and ‘certain additional manufacturing related process information’.

Europe approved its first cancer biosimilar Truxima (CT-P10; rituximab) in February 2017. An insulin glargine biosimilar, Lusunda, and two teriparatide biosimilars, Movymia and Terrosa, received European Commission (EC) approval in January 2017. Three adalimumab biosimilars, Amgevita, Solymbic and Imraldi received EC approval in March 2017 and August 2017, respectively. The EC also approved the etanercept biosimilar Erelzi and the rituximab biosimilars Blitzima, Ritemvia, Rituzena (previously Tuxella), Rixathon and Riximyo in June 2017. The insulin lispro biosimilar, Insulin lispro Sanofi, also received EC approval in June 2017 and the trastuzumab biosimilar Ontruzant received EC approval in November 2017. In addition, the adalimumab biosimilar, Cyltezo (BI 695501), received EC approval in November 2017.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of the bevacizumab biosimilar Mvasi (ABP 215) in November 2017 and for the trastuzumab biosimilar Herzuma (CT-P6) in December 2017. The agency is also currently reviewing biosimilar applications for adalimumab, infliximab, insulin glargine, pegfilgrastim and trastuzumab.

The year did not start so well for Sandoz, when it had to withdraw the marketing application for its pegfilgrastim biosimilar (Zioxtenzo) from EMA, after the agency expressed doubts about its biosimilarity and manufacturing. However, it ended on a much more positive note when in October 2017 EMA accepted the resubmission. India-based biologicals specialist Biocon also withdrew the European Union (EU) marketing applications for its trastuzumab and pegfilgrastim biosimilars in August 2017 after failing a good manufacturing practice (GMP) inspection by the French inspecting authority (L’Agence nationale de sécurité du médicament et des produits de santé, ANSM).

EMA also extended the indications for etanercept biosimilar Benepali to include juvenile idiopathic arthritis and paediatric plaque psoriasis.

Merck Sharp & Dohme (MSD) announced in May 2017 its intention to launch the infliximab biosimilar Renflexis in Australia in the second half of 2017. Renflexis is the second infliximab biosimilar to receive Therapeutic Goods Administration (TGA) approval. Hospira’s infliximab biosimilar, Inflectra, received approval in Australia back in August 2015.

In August 2017, Sandoz, the generics division of Novartis, announced that its etanercept biosimilar, Erelzi, is now available in Canada, after receiving approval from Canada’s medicines regulator, Health Canada. Erelzi is the second etanercept biosimilar approved by Health Canada. Merck Canada’s Brenzys (etanercept) was the first etanercept biosimilar approved by the agency back in August 2016.

Elsewhere, in Indonesia, generics maker Kalbe Pharma (Kalbe) announced the launch of a basal analogue insulin ‘copy biological’ on 25 March 2017.

In South Korea, Samsung Bioepis announced that it had received approval for its adalimumab biosimilar, Hadlima (SB5), and for its trastuzumab biosimilar, Samfenet (SB3), from the Korean Ministry of Food and Drug Safety (MFDS, formerly the Korea Food and Drug Administration) in November 2017.

Celltrion received approval from China’s Food and Drug Administration (CFDA) to start clinical trials for its infliximab biosimilar, Remsima (CT-P13), in the country. This will make it the first foreign company to initiate clinical trials of an antibody biosimilar in China.

Japan-based generics maker Nichi-Iko Pharmaceutical gained Japanese approval for its infliximab biosimilar (NI-071) in September 2017. The Japanese medicines regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA), is also reviewing applications for approval of Mochida Pharmaceutical’s etanercept biosimilar (LBEC0101), Celltrion’s biosimilar trastuzumab Herzuma (CT-P6) and JCR Pharmaceuticals’ agalsidase beta biosimilar (JR 051).

Russia’s Ministry of Health approved Biocad’s interferon beta-1a non-originator biological, BCD-033, in march 2017.

In a landmark decision, South Africa’s Medicines Control Council (MCC) approved the country’s first non-originator biological, filgrastim, from Teva Pharmaceutical Industries.

Meanwhile, India’s drug regulator, the Drugs Controller General of India (DCGI), granted marketing approval for a rituximab ‘similar biologic’ (Acellbia) from Russian biotechnology company Biocad in June 2017, follow by Biocon announced in November 2017 the launch of its product Krabeva, a ‘similar biologic’ of bevacizumab, in India.

In June 2017, Biocad announced that it had obtained marketing authorization for its rituximab ‘similar biotherapeutic product’ in Bolivia and Honduras under the trade name Usmal.

Finally, the World Health Organization (WHO) announced in September 2017 that it would be launching its pilot project for prequalifying biosimilars in October 2017. This move says the organization, is a ‘step towards making some of the most expensive treatments for cancer more widely available in low- and middle-income countries’.

Delaying biosimilars

In an effort to delay or prevent competition from biosimilars originator companies have come up with many different strategies.

A provisional statement from the UK Competitions and Markets Authority (CMA) says that MSD ran an anticompetitive discount scheme for anti-inflammatory drug Remicade (infliximab). In an attempt to defend itself from cheaper biosimilar versions, MSD launched a discount scheme for Remicade cutting prices in the UK by around a quarter through rebates and discounts to the UK’s National Health Service (NHS). MSD abused its dominant position in the market by doing this, says CMA.

Citizen’s petitions
Several companies have petitioned FDA during 2017, a process that some believe to be an attempt to delay or prevent the approval of biosimilars.

In April 2017, Apotex and its biosimilars unit Apobiologix, submitted a Citizen Petition to FDA requesting that the agency requires all biosimilar applicants referencing Neulasta (pegfilgrastim) to ‘conduct their comparative clinical efficacy studies (including pharmacokinetics (PK) and pharmacodynamics (PD) studies and immunogenicity studies) in at least one intended patient population’.

Danish pharmaceutical company Novo Nordisk has asked FDA to require clinical trials for biosimilar applications for its blockbuster diabetes drug Victoza (liraglutide). The company argues that the manufacturing process for Victoza, whose patent expires in 2022, is so complex that equivalence of a biosimilar cannot be established without clinical trials.

A study of citizen petitions submitted to FDA over the last 12 years found that such petitions are being used by drug companies ‘in a last-ditch effort to hold off competition’, often being submitted in the last year before approval of a competitor.

Pay-for-delay
Pay-for-delay deals occur when brand-name companies pay biosimilars companies challenging their patents to delay the introduction of lower-cost biosimilars in return for a payment or payments from the originator company. During 2017, several companies entered into deals that could possibly be considered pay-for-delay deals.

One such significant deal was made in September 2017 between Amgen and pharma giant AbbVie. The companies announced that they had reached a ‘global resolution’ ending all patent litigation regarding AbbVie’s blockbuster arthritis drug Humira (adalimumab). The settlement means that Amgen’s adalimumab biosimilar will be launched in the EU on 16 October 2018, but will only be launched in the US on 31 January 2023. It has been estimated that this delay could cost the US Centers of Medicare and Medicaid Services (CMS) at least US$1.48 billion.

In a landmark decision, the US Supreme Court ruled that biosimilars makers will be able to give notice to the originator manufacturer before FDA has given final approval of the biosimilar. Brand-name biologicals makers had been trying to gain a ruling that the 180-day notice could only be given after the 12-year exclusivity period ended.

Biologicals naming

Naming for biologicals remains a contentious issue during 2017.

The World Health Organization (WHO) introduced the concept of a biological qualifier (BQ) proposing a possible four-letter alphabetic code for all biologicals back in 2014. Some disagree with this proposal for distinct naming. However, others have commended WHO for their leadership in proposing a global solution to this problem and await its availability for implementation [1].

FDA issued its final guidance on the non-proprietary naming of biological products – requiring the use of suffixes – in January 2017 [2, 3]. However, healthcare organizations have expressed their ‘grave concerns’ over the ‘enormous financial consequences’ of the guidance, which they believe ‘will easily run into the billions of dollars’.

A survey carried out by the ASBM on the naming and labelling of biologicals with US pharmacists, the results suggest that when a biosimiar and the reference product share the same non-proprietary name could lead to confusion. This is because the two products could be considered identical, could be expected to produce the same results, could be used interchangeably and would be approved for all the indications of the reference product [4]. The pharmacists surveyed, however, also considered it very important to include on the product label clinical data to support whether or not the product was a biosimilar and information regarding whether or not the biosimilar and originator are interchangeable. On the other hand, US prescribers were not in complete agreement on how biologicals, whether originators or biosimilars, should be named. However, 79% of physicians rated it as important to include on the label whether the product is a biosimilar or not and whether the product is interchangeable [5].

In a survey of 160 prescribers of biologicals in Australia, over three quarters agreed that the country’s TGA should insist on distinct non-proprietary scientific names for all biosimilars and reference products. Most (61%) wanted TGA to play a major role in naming biosimilars and believed TGA should be responsible for recommendations on pharmacy-level substitution, while only a third (33%) thought that Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) should be responsible. Responders also generally agreed that biosimilars should be distinguished from originators with either the same non-proprietary scientific name and a differing prefix or suffix, or with a completely unique name [6].

Australia’s TGA opened a consultation on how to name biologicals in July 2017. In a survey of 160 prescribers of biologicals in Australia, over three quarters agreed that the country’s TGA should insist on distinct non-proprietary scientific names for all biosimilars and reference products.

Substitution/interchangeability

Automatic substitution is the practice by which a medicinal product other than the one specified on the prescriptions is dispensed to the patient, without the prior informed consent of the treating physician [7].

In a survey of 160 prescribers of biologicals in Australia, nearly all prescribers thought that they and their patients should decide which biological is dispensed and that they should be notified of any substitution by the pharmacist [6].

Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. In terms of biologicals, this could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another [8].

Also, interchangeability can be defined as the medical/pharmaceutical practice of switching one medicine for another that is equivalent, in a given clinical setting. A product is considered to be interchangeable if it can be administered or dispensed instead of another clinically equivalent product without significant risk of an adverse health outcome.

Europe and the US have different approaches on interchangeability of biosimilars [7]. In the US interchangeability is defined in law as part of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) and FDA may approve a product as interchangeable. In Europe, on the other hand, interchangeability is defined in a consensus information document on biosimilars and decisions on the interchangeability or substitution of biosimilars and originator biologicals are not made by EMA, but at the national level. Although most European Member States do not allow automatic substitution, and many have introduced rules to avoid automatic substitution of biosimilars, some have allowed limited substitution of biosimilars. The lack of harmonization for the interchangeability of biosimilars across the world introduces confusion for stakeholders and developers possibly delaying access to life-saving treatments [9].

A global survey carried out by Pfizer examined biosimilar pharmacy-mediated substitution in 82 countries. The survey found that in Europe, North America and Asia-Pacific, many countries have developed specific policies on pharmacy-mediated substitution relating to biosimilars. Whereas, in Latin America, Africa and the Middle East, there are largely no policies on this matter; the focus appears to remain on the development of general biosimilar regulations and guidances. Pfizer concluded that ‘due to the complexity of biologicals, it is our opinion that pharmacy-mediated substitution is not appropriate unless stringent regulatory and legal criteria additional to appropriate biosimilarity requirements can be met, as outlined in the International Federation of Pharmaceutical Manufactourers & Associations’ (IFPMA) position paper on pharmacy-mediated substitution’ [10].

In July 2017, Germany-based Boehringer Ingelheim announced that the first patient had been enrolled into the phase III VOLTAIRE-X interchangeability study of its adalimumab biosimilar (BI 695501). The company says the trial ‘is the first study in the US to investigate an interchangeability designation for an adalimumab biosimilar candidate’.

Agency guidances and supports on biosimilars

FDA finalized its guidance detailing the agency’s requirements for the non-proprietary naming of biological products in January 2017. In the finalized guidance, which was released on 12 January 2017, FDA says it will assign a non-proprietary name for all originator biologicals, related biologicals and biosimilars that includes an ‘FDA-designated suffix’. The ‘proper name’ will consist of a combination of the ‘core name’ and distinguishable suffix, which will be ‘devoid of meaning’ and be ‘composed of four lowercase letters’. The agency rejected citizen petitions urging the agency to allow biosimilar sponsors to use the same non-proprietary names as their reference products.

The agency also published draft guidance on the interchangeability of biosimilars with their reference products in January 2017. However, to date, no biosimilars are as yet approved as interchangeable and concerns have been raised regarding extrapolation, as well as interchangeabilty, switching and provider notification. The document was initially released for a 60-day comment period (until 20 March 2017), but subsequently extended the period until 19 May 2017. The agency received 52 comments on the guideline covering concerns about extrapolation of indications, switching, labelling and naming, post-marketing studies and FDA’s requirements for interchangeability. Final guidance on pharmacology data for biosimilarity was also published. The Draft guidance on statistical approaches to evaluate similarity for biosimilars and guidance on biological manufacturing changes was also issued by FDA. Comments from stakeholders on the statistical approaches guidance indicated that they want it to be more specific and narrower in scope.

FDA released a Biosimilar User Fee Act II (BsUFA II) performance goals letter, which outlined how the BsUFA II agreement would ‘help provide FDA with the resources needed to enhance the science-based review of new biosimilars, which will help increase competition in the marketplace to the benefit of patients’. The BsUFA calls for biosimilars makers to pay fees annually to FDA in the same way as brand-name drugmakers do. The agency released the statement of work for a comment period of 30 days, until 31 July 2017.

FDA also updated its ‘Purple Book’. The ‘Purple Book’ is a set of lists of licensed biological products and biosimilars that is meant to be the biological equivalent of the ‘Orange Book’, which lists pharmaceuticals and their generic drug equivalents.

EMA announced that it is planning to provide sponsors with tailored scientific advice on the development of biosimilars as part of a pilot programme that will be launched in February 2017. Specifically, the pilot will offer biosimilar developers advice on the studies and tests they should conduct, based on the available quality, analytical and functional data for the medicine. EMA expects this approach to better support the stepwise development of biosimilars, as recommended in EU guidelines.

Pharmacovigilance is an important issue for biologicals, including biosimilars. It is a legal requirement for all biologicals: European PV legislation (EU No. 520/2012) provided several obligations, which were followed by the good pharmacovigilance practice guidelines released by EMA [11].

The Indian Ministry of Health revised its guidelines for approving ‘similar biologics’. The guideline was updated in order to make the regulatory pathway more robust and to align the guidelines further with global guidelines for biosimilars.

Finally, the challenges of adapting European Pharmacopoeia (Ph. Eur.) monographs for biologicals and how they can be overcome was a subject discussed by Dr Emmanuelle Charton, Head of Division of the European Pharmacopoeia Department at the European Directorate for the Quality of Medicines & HealthCare (EDQM), during 2017 [12].

Clinical trials for biosimilars

Many clinical trials for biosimilars have been carried out during 2017. As increasing evidence on the efficacy and safety of biosimilars becomes available it is hoped that trust in biosimilars will increase. Some of the clinical trials for biosimilars carried out during 2017 are summarized below.

Adalimumab
A phase III study of an adalimumab biosimilar (CHS 1420) from Coherus showed, according to the company, that the biosimilar is ‘similar’ to AbbVie’s Humira (adalimumab).

While Pfizer’s adalimumab biosimilar (PF-06410293) demonstrated, according to the company, equivalent efficacy for treatment of those with severe active rheumatoid arthritis, as measured by the American College of Rheumatology 20 (ACR20) response rate at Week 12.

A phase III study of another proposed adalimumab biosimilar (GP2017) from Sandoz was also reported to have met its primary endpoint ‘demonstrating equivalent efficacy’ to Humira (adalimumab).

Results from the phase III VOLTAIRE-RA trial ‘confirmed’ that Boehringer Ingelheim’s ‘adalimumab biosimilar candidate BI 695501 and Humira have similar efficacy, safety and immunogenicity in patients with moderately-to-severely active rheumatoid arthritis’. Cyltezo (BI 695501) was approved by FDA in August 2017 and by EMA in September 2017.

A phase III study comparing ABP 501 to Humira in rheumatoid arthritis patients demonstrated equivalent response in improvement in Psoriasis Area and Severity Index 75% (PASI75) scores and supported regulatory approval. Amjevita (ABP 501) was approved by FDA in September 2016 and by EMA in March 2017.

Bevacizumab
A study has shown that bevacizumab-containing regimens improve survival in advanced non-squamous non-small cell lung cancer (NSCLC) patients. Amgen/Allergen’s bevacizumab biosimilar Mvasi (ABP 215) was approved by FDA in September 2017 and by EC in January 2018.

Filgrastim
Real-life data has been shown to support the efficacy and safety of biosimilar filgrastim. A study of biosimilar filgrastim in diffuse large B-cell lymphoma (DLBCL) patients showed that ‘the efficacy and safety of biosimilar filgrastim in real-life practice in patients with DLBCL are similar to the known efficacy and safety profile of reference filgrastim’. In addition, the researchers added that ‘this supports the use of biosimilar filgrastim in real-world use and extends the efficacy and safety from its clinical development program[me]’.

Infliximab
Results of a phase III study of Celltrion’s infliximab biosimilar (Remsima; CT-P13) ‘indicate that the safety and efficacy of CT-P13 in patients with moderate-to-severe Crohn’s disease (CD) is comparable to those treated with reference infliximab’, according to the company.

A systematic review and meta-analysis of Celltrion/Hospira’s infliximab biosimilar, Remsima/Inflectra also found it to be safe and effective in the treatment of inflammatory bowel diseases (IBD). The authors concluded that the results of their study ‘support the use of CT-P13 in the treatment of IBD’.

A study comparing infliximab biosimilar (Remsima, CT-P13) to originator infliximab (Remicade) in patients with active CD found that ‘CT-P13 was similar to [originator infliximab] in terms of CDAI-70 [70% reduction in Crohn’s Disease Activity Index score], CDAI-100 and clinical remission up to Week 6 in patients with CD’.

In a study of real-life experience with CT-P13 carried out in Hungary results suggest high response and remission rates similar to those previously reported with the originator biological.

Pegfilgrastim
Spanish biosimilars developer Cinfa Biotech (Cinfa) announced in May 2017 that results from the second phase I study of its pegfilgrastim biosimilar (B12019) had met its primary endpoints. According to Cinfa, ‘the study met its primary endpoints: area under the effect curve (AUEC0-last) for PD and anti-drug antibody rate (ADA) for immunogenicity, confirming comparability to Neulasta’ [13].

In November 2017 Cinfa presented additional clinical data for B12019. The results showed, according to Cinfa, that ‘the number of ADA-positive subjects was very low for both, B12019 and Neulasta. No imbalance was observed between the study drugs after repeated dosing’ and ‘neither anti-filgrastim nor neutralising antibodies were detected for B12019 or Neulasta’.

Apobiologix published analytical results demonstrating the similarity of their pegfilgrastim product to Amgen’s Neulasta (pegfilgrastim). The company said that the first step towards establishing biosimilarity of this pegfilgrastim molecule to Neulasta, namely demonstration of analytical similarity, appears to have been met. The company says that its biosimilar is also under active review by FDA.

Ranibizumab
In February 2017, Xbrane Biopharma reported positive in vitro biosimilarity data for its ranibizumab biosimilar, Xlucane. The comprehensive in vitro biosimilarity study was carried out with several pilot scale R & D batches of Xlucane versus several batches of the reference product. The study was carried out in accordance with EMA and FDA biosimilar guidelines.

Rituximab
CT-P10 (Truxima) is the first rituximab biosimilar and was approved in Europe for all licensed indications in February 2017.

A study of the rituximab biosimilar Truxima (CT P10) ‘demonstrated’, according to the authors, similar PKs and safety when administered in combination with cyclophosphamide, vincristine and prednisone in patients with newly diagnosed advanced follicular lymphoma.

A pharmacovigilance study of Novex, a rituximab medicamento biológico similar approved in Argentina was also carried out. The authors found that ‘the biosimilar product Novex showed a safety profile similar to what has been described with the reference product’. They therefore concluded that, ‘in terms of tolerability, the biosimilar product has a comparable profile with the reference product’.

Positive phase I results for rituximab biosimilar CT-P10 in patients with rheumatoid arthritis demonstrated, according to Celltrion, that the clinical profile of CT-P10 is comparable to reference rituximab in patients with rheumatoid arthritis over an extended treatment duration.

A network meta-analysis was used by researchers from Italy to ‘reinforce the clinical data available’ for the equivalence of the rituximab biosimilar CT-P10. The authors concluded that ‘the clinical consequences generated by our network meta-analysis should be seen as a reinforcement of the clinical evidence available on the biosimilar and as a confirmation of the homogeneity of the overall clinical material included in this effectiveness assessment’.

Tocilizumab
A study carried out by researchers in China compares China’s Hisun’s tocilizumab copy biological (HS628) to the originator Actemra (tocilizumab). They found the copy biological to be highly similar in terms of its physical, chemical and biological characteristics. The authors therefore concluded that this tocilizumab copy biological is highly similar to the originator drug, both in terms of its biological function and physicochemical properties.

Trastuzumab
In January 2017, Mylan and Biocon reported that the results from their phase III HERiTAge study ‘confirm the efficacy, safety and immunogenicity of MYL-1401O, in comparison to branded trastuzumab’.

Results of a phase III clinical study of Celltrion’s biosimilar trastuzumab candidate CT-P6 demonstrated the ‘similarity’ of the efficacy and safety compared to the originator biological (Herceptin) in patients with HER2+ breast cancer. The company submitted its marketing application to EMA for approval back in November 2016 and to FDA in July 2017.

In September 2017, biotech giant Amgen and partner Allergan presented positive data from a phase III study of their trastuzumab biosimilar (ABP 980) compared to Herceptin (trastuzumab). According to local review, 48.0% and 40.5% of patients in the ABP 980 arm and Herceptin arm, respectively, achieved pathologic complete response. Frequency, type and severity of adverse events were also similar between ABP 980 and Herceptin. The marketing applications for ABP 980 were submitted to EMA and FDA in March and July 2017, respectively.

Pharma giant Pfizer announced in September 2017 positive results from the pivotal phase III study of its candidate trastuzumab biosimilar (PF-05280014). Pfizer says that ‘data from the REFLECTIONS B327-02 study demonstrates equivalence in objective response rate (ORR) for patients with HER2-positive metastatic breast cancer’.

Extrapolation

A topic that is often questioned by prescribers is extrapolation of indications [14, 15]. EMA has stated that ‘if clinical similarity can be shown in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product may be possible’ under certain conditions.

Paediatricians from Europe have expressed concern about the extrapolation of the limited amount of available clinical data from adults with rheumatologic diseases to children with IBD. Therefore, the Erasmus Medical Center, in collaboration with The Netherlands Organisation for Health Research and Development and biosimilars maker Hospira, is carrying out a study to investigate the benefits and risks of the use of infliximab as first-line use for children with active perianal fistulising CD.

Another study discussed the scientific rationale for extrapolation of indications in the case of Celltrion’s rituximab biosimilar Truxima (CT-P10). Truxima was approved for all indications held by the reference rituximab, Roche’s MabThera/Rituxan (rituximab), based on the totality of evidence collected in the comprehensive comparability exercise. The rationale for extrapolation included the use of rheumatoid arthritis as an appropriate indication for comparison, the role of B cells in the pathology of disease for all indications and the comparability of CT-P10 and Rituxan to induce cytotoxicity, antibody-dependent cellular cytotoxicity and apoptosis.

In January 2017 The European Society of Medical Oncology (ESMO) published a position paper about biosimilars. With respect to interchangeability and switching, ESMO says this should only be permitted if: (1) the physician is well-informed about the products; (2) the patient is fully briefed by the physician; and (3) a nurse is closely monitoring the changes and tracking any adverse events.

Switching

The often contentious issue of switching patients from originator biologicals to biosimilars was also a topic of interest during 2017. 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.

Attitudes to switching are changing. The European Crohn’s and Colitis Organisation (ECCO) published results of a consensus meeting held in October 2016 in Vienna, Austria in which they support switching from reference infliximab to biosimilar infliximab. The statement marks a significant shift in attitude from the previous ECCO position statement, which advised that switching from an originator biological to a biosimilar was inappropriate and called for more data on the safety and benefit of biosimilars in general.

The European Federation of Pharmaceutical Industries and Associations (EFPIA), European Biopharmaceutical Enterprises (EBE) and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) also issued a joint position paper entitled ‘Considerations for physicians on switching decisions regarding biosimilars’. The associations conclude that the ‘physician is best placed to assess the patient, disease and product, when deciding if and how to switch the biological product that a patient is receiving for another one’. They add that ‘effective pharmacovigilance for biologic[al]s is always important, especially when there are multiple treatment options available’.

A task force in The Netherlands came to the conclusion that switching is safe and effective, but that multiple switches should be assessed and that no switches should be made without the knowledge of patients/rheumatologists.

The Nordic countries have been seen as leading the way when it comes to switching and substitution of biosimilars in Europe, but even within these countries there are differences in the way they approach switching to biosimilars. However, despite a reluctance to switch patients to biosimilars in many countries, financial pressures and the growing body of evidence supporting switching may change the tide in Europe in the near future.

Just a few of the clinical trials studying switching to biosimilars carried out during 2017 are summarized below.

Infliximab
A UK study has shown that IBD patients can be safely switched from originator infliximab, Johnson & Johnson and Merck’s Remicade, to biosimilar infliximab using a managed-switching programme.

A study of the infliximab biosimilar Remsima showed, according to the authors, similar ‘safety and survival’ of Remsima compared to Remicade. The data from this study are similar to those shown in the pivotal PLANETRA and PLANETAS trials, which led the authors to conclude that ‘these data support an increasingly widespread use of this biosimilar in any patient profile’.

A review of post-marketing experience with the infliximab biosimilar CT-P13 evaluated more than 600 IBD patients, 39 paediatric patients and 183 switched from originator infliximab. The mean efficacy was 72%, the rate of adverse events 10.4%, and the rate of infusion reactions was 5.5%. These results are in agreement with data presented for the NOR-SWITCH study, which showed that the group of patients that were switched to Remsima had comparable efficacy and safety to those who remained on the originator biological.

Similarly, a study by researchers from Denmark found that switching from originator to biosimilar infliximab (CT-P13) had ‘no negative impact on disease activity’.

Results of the NOR-SWITCH study, published in May 2017, also failed to find inferiority when switching from originator infliximab to CT-P13. The study followed recommendations from the Norwegian Health Authorities, which stated that CT-P13 be used for patients starting treatment with infliximab [16].

Results from another switching study for CT-P13 in CD patients ‘demonstrated that the infliximab serum concentration of the biosimilar was non-inferior to the infliximab concentration of the reference infliximab 16 weeks after switching in patients with CD’.

Results of a phase III extension study also showed that CT-P13 is comparable in efficacy and safety to Remicade in switched IBD patients, according to Celltrion.

Similarly, results of an observational study showed that switching from Remicade to CT-P13 is, according to the authors, ‘efficacious and well tolerated in patients with CD or ulcerative colitis (UC) for up to 12 months’.

However, authors from the Division of Rheumatology at the Hospital of Prato, Italy reported on three patients with Behçet’s disease that experienced disease relapses after switching from the originator infliximab, Remicade, to biosimilar infliximab.

Etanercept
In July 2017, real-world switching data for etanercept biosimilar Benepali (SB4) compared to Amgen/Pfizer’s arthritis blockbuster Enbrel (etanercept) demonstrated ‘sustained efficacy and safety, and high acceptance and adherence in patients initiating treatment with Benepali (etanercept)’, according to Biogen.

However, a study carried out by researchers from Denmark found that switching from originator to biosimilar etanercept does not work for all patients. During 2016, non-medical switching of patients treated with originator etanercept (Enbrel) to Benepali was implemented in Denmark. However, although their study showed unchanged efficacy after switch in 76 out of 85 cases, in nine cases significant loss of efficacy and/or adverse events were recorded during the first four months after the switch. A subsequent investigation, which included 2,030 patients treated with etanercept 1-year post switch, found that in switchers, 276 patients (18%) stopped treatment with Benepali during follow-up, mainly due to loss of efficacy (54%) or adverse event (28%).

Researchers from The Netherlands found that ‘open label non-mandatory transitioning from Enbrel to SB4 showed a statistically significantly but clinically not relevant lower retention rate compared to a historical cohort, similar to retention seen after mandatory infliximab transitioning’. They concluded that ‘non-mandatory transitioning, when executed optimally, might therefore be an attractive alternative to mandatory transitioning’.

Rituximab
In November 2017, results of a phase III extension study showed that Celltrion’s rituximab biosimilar (Truxima, CT-P10) is comparable to Roche’s MabThera/Rituxan, according to the South Korean biotechnology company.

Another single-arm, open-label extension study found comparable efficacy and safety in patients switched to infliximab biosimilar CT-P10. This study showed, according to the authors, that long-term treatment with CT-P10 was efficacious and well-tolerated by patients, supporting the results of the phase I randomized controlled trial.

Results of another phase III extension study showed, according to Celltrion, that their rituximab biosimilar (Truxima, CT-P10) is comparable to MabThera/Rituxan as determined by the Disease Activity Score for 28 joints C Reactive Protein (DAS28 CRP) improvement, as well as American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response rates. This switching data in rheumatoid arthritis patients supports the long-term efficacy and safety of Truxima.

Researchers from Argentina, Brazil, Germany, the UK, and the US investigated switching from originator biologicals to biosimilars. They carried out a MEDLINE/Web search to identify studies where healthy volunteers or patients receiving adalimumab, etanercept, infliximab or rituximab were switched between originator biologicals and biosimilars. The authors concluded that ‘switching data is starting to become available; mostly with infliximab but also emerging for other drugs’. In addition, the authors believe that ‘while initial transition data confirm maintenance of efficacy and safety, additional data from clinical and real-world switching studies, especially of switching between biosimilars, are required, as is continuing pharmacovigilance’. They added that ‘any switching should remain a clinical decision made jointly by the treating physician and patient on an individual patient basis supported by scientific evidence’.

Labelling and reimbursement

Labels on medicinal products contain information for pharmacists, physicians and patients. This information is presented in the Summary of Product Characteristics (SmPC), the Patient Leaflet (PL) and the immediate label on the outer product packaging [17].

In June 2017, the European Association for Bioindustries (EuropaBio) announced that it had ‘developed recommendations for changes to the SmPC of biosimilars that would result in an enhanced level of transparency in the label’. Taking into account the results of a survey of physicians’ labelling preferences, the association has recommended adding a statement with the definition of biosimilarity, adding a direct link to the European public assessment report (EPAR) next to the biosimilarity statement and moving the biosimilarity statement to the top of the SmPC.

Pharmaceutical pricing and reimbursement policies aim to improve the rational use of medicines and keep pharmaceutical spending under control. In the EU the design and implementation of pharmaceutical policies are implemented at a Member State level [18]. Although policies for biosimilars might be expected to be similar to those for generics, a survey of European countries showed that this is the case for only some policies and varies by country [19].

An issue highlighted that could present issues for US oncologists was that of reimbursement for oncology biosimilars in the US. The US lacks payer infrastructure facilitating the automatic substitution of brand-name biologicals and biosimilars. The complex distribution chain for biologicals may also hamper widespread use of biosimilars. Finally, it is unclear to what extent biosimilar makers will challenge makers of originator biologicals in select therapeutic classes. These issues, according to Dr Rena Conti, Associate Professor of Health Policy and Economics in the Department of Paediatrics at the University of Chicago, could place oncology practices ‘on the front lines of adjudicating whether to prescribe biosimilars to treat cancer’.

Senator Pat Roberts and Representatives Joe Barton and Anna Eshoo, along with a delegation of 52 House Members and nine Senators, have asked the CMS to reverse its biosimilars policy. The rule (CMS-1631-P) assigns a single code [Healthcare Common Procedure Coding System (HCPCS)] to all biosimilars of a particular reference product and reimburses them based on the weighted average of their average sales price under Medicare Part B. However, concerns have been raised that this coding policy ‘presents a major departure from previous CMS policy and unfairly disadvantages non-interchangeable biosimilars’, according to the GPhA and its Biosimilars Council. Concerns have also been raised that the rule would discourage innovation, erect barriers to developing biosimilars and create safety issues due to the inability to differentiate between biosimilars and reference (brand-name) products. Groups representing physicians in the US have also urged the CMS to revise its policy of assigning a single code to all biosimilars. Instead they urge the CMS to adopt unique HCPCS billing codes, otherwise known as J–Codes.

Collaborations and investment in biosimilars

Collaborations with respect to biosimilars and investment in biosimilars were also popular during 2017.

Mylan reached an agreement with Polish biotechnology company Mabion for the exclusive right to commercialize their rituximab biosimilar candidate in the EU.

India-based Biocon announced in January 2017 that it had been awarded a contract by the Malaysian Ministry of Health to supply recombinant human insulin formulations to the country, a deal reportedly worth US$68 million.

In February 2017, India-based generics maker Aurobindo announced its first foray into the biosimilars field with the acquisition of four cell culture-derived biosimilars from Swiss-based TL Biopharmaceutical AG.

In July 2017, Daiichi Sankyo announced that it was ending its partnership with Coherus BioSciences for a biosimilar to Amgen’s arthritis drug Enbrel (etanercept) in Japan.

Biotech giant Amgen and China-based Simcere Pharmaceutical Group (Simcere) announced in September 2017 an exclusive agreement to co-develop and commercialize four copy biologicals in China.

Germany’s drugmaker Merck KGaA (Merck Group) announced that it would sell its biosimilars division. Then in September 2017 Fresenius Kabi announced that it had ‘successfully closed the acquisition of Merck KGaA’s biosimilars business’. Merck KGaA announced that it was extending its strategic alliance for biopharmaceutical manufacturing and biologicals process development with Samsung BioLogics.

The CinnaGen Group has committed to opening a new production facility in Turkey under the name of CinnaGen Ilac by the end of 2017. With an investment of US$30 million, the new venture is expected to launch its first biologicals in 2019.

Factors affecting and supports required for uptake of biosimilars

The future for biosimilars looks promising. There are an increasing number of clinical trials being carried out for biosimilars and an increasing number of global biosimilar approvals. In addition, cost analyses are proving that biosimilars have the potential to provide significant savings for healthcare systems around the world. There is increasing evidence that biosimilars are safe for patients. However, healthcare professional and patient opinions, as well as national and local guidelines, levels of funding and differing approaches to healthcare management can influence access to biosimilars in different Member States of the EU.

A study of patients taking etanercept to treat rheumatoid arthritis or psoriasis in the UK has shown that there are substantial savings to be made by using the etanercept biosimilar (GP 2015). The results indicated that GP 2015 ‘may offer cost savings of between GBP 4.8 million (10% discount scenario) and GBP 14.3 million (30% discount scenario)’. This could enable between 568 (in 10% discount scenario) and 2,191 (in 30% discount scenario) more patients benefitting from treatment with etanercept.

Another study using a budget impact model estimated that rituximab biosimilar CT-P10 could save Europe Euros 90 million in its first year alone. The authors, however, concluded that cost is not the only factor that determines uptake of biosimilars. The attitudes of patients, healthcare professionals and payers also play a part.

Competition between brand-name biologicals and biosimilars has the potential to reduce future cancer costs, according to researchers from Italy. However, to really benefit from biosimilars and increase their use, confidence in the development of biosimilars needs to be increased.

The use of biosimilars, however, continues to be limited, and the scepticism of prescribers and patients seem to be linked to the uncertainty of the risk–benefit profile of biosimilars. In the case of epoetins, used in the management of anaemia in the nephrology and oncology settings, the results of a recent study showed no difference between biosimilars and originators on relevant effectiveness and safety outcomes.

In Italy, real-world data revealed heterogeneous uptake of first generation biosimilars over time and across regions of Italy [20]. While in Germany the Drug Commission of the German Medical Association developed a practical guidance for the therapeutic use of biosimilars in order to try and increase their adoption in the country [21].

A study of major lessons learned from Zarxio’s US launch revealed that biosimilar manufacturers are likely to see limited initial acceptance and uptake of their competing products in the near term; at present it is anticipated that biosimilar companies will modestly discount (20–30%) their products versus the reference product until there are multiple biosimilar competitors. The US biosimilar market resembles a ‘branded’ market, rather than a ‘generics’ market; and biosimilars will secure favoured tier coverage and/or formulary exclusivity from payers as biosimilar manufacturers increase rebates [22].

Education with respect to biosimilars is thought to be a major issue. A survey of hospital specialists and pharmacists concluded that ‘educational interventions will be urgently required with the forthcoming approval of biosimilars under active development to avoid the risk of patients continuing to use more expensive drugs’.

Moorkens et al. identified and described different barriers to the market access of biosimilar monoclonal antibodies (mAbs) in the EU. They concluded that barriers could be reduced when more transparency and communication/education is used in all steps toward market access in order to increase trust in biosimilar mAbs by all stakeholders. Only then, will biosimilar mAbs be able to fully live up to their cost-saving potential.

In order to increase uptake of biosimilars physicians need to be better educated about biosimilars, national regulatory authorities and government/regional healthcare providers need to promote biosimilars, and national professional societies should favour them. It is therefore important to get professional bodies on board when it comes to biosimilars.

In Europe, in January 2017, ESMO published a position paper on biosimilars saying that ‘biosimilars create opportunities for sustainable cancer care’. The position statement outlines the approval standards for biosimilars, how to safely introduce them into the clinic and the potential benefits for patients and healthcare systems. It covers aspects related to definition, forms of biosimilars, labelling, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, responsibilities among prescribers and pharmacists, potential impact on financial burden in healthcare and the current scenario and future prospects of biosimilars in Europe and the rest of the world.

In January 2017, GaBI and the Association of the British Pharmaceutical Industry (ABPI) hosted a roundtable on patient and disease registries in London, UK. Stakeholders agreed that patient registries, data collection at the point of care and the ability to link between registries and routine clinic and hospital data were important goals. Achieving these goals will require an aligned vision amongst stakeholders, appropriate resourcing and a sustainability model, extensive collaboration and linking across registries, and the universal implementation of standards for record headings and clinical terms [23]. GaBI also organized the First ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products in July 2017, Bangkok, Thailand in collaboration with ASEAN (Association of Southeast Asian Nations) [24]. In addition, GaBI organized a scientific meeting in Colombia with INVIMA (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) [25]. with the aim of strengthening knowledge of quality assessment of biosimilars in Colombia.

In March 2017, the European Parliament voted on a resolution to strike a better balance between EU countries’ public health interests and those of the pharmaceutical industry. The resolution on ‘Options for improving access to medicines’ calls for Member States to encourage competition from generics and biosimilars by removing barriers and adopting uptake measures.

The EC held its third workshop on biosimilars in Brussels, Belgium in May 2017, with the aim of encouraging equitable and timely access to biosimilars in Europe.

In September 2017, NHS England released a ‘Commissioning framework for biological medicines (including biosimilar medicines)’. The guidance framework recommends that at least 90% of new patients be prescribed the ‘best value biological medicine within three months of launch of a biosimilar medicine’. In October 2017, the UK also launched a campaign, called ‘Focus on Biosimilars’, to promote research on biosimilars.

The British Oncology Pharmacy Association (BOPA) announced in February 2017 the publication of its position statement and implementation Guidelines on Biosimilar Monoclonal Antibodies. In its guideline document BOPA states that ‘oncology pharmacy teams are key to ensuring the safe, successful and timely adoption of biosimilar monoclonal antibodies (mAbs)’. BOPA’s position is that ‘biosimilar mAbs are therapeutically equivalent to the originator molecules and can and should be used for all commissioned indications, provided pharmacovigilance safeguards are in place, e.g. branded prescribing’.

Ireland is also to publish a consultation on biosimilars, with the aim of increasing their use in order to provide significant savings for the Irish healthcare budget. The country’s Department of Health (DoH) also started a consultation on its biosimilars policy. The DoH is asking for feedback on the need for national, statutory or clinical prescribing guidelines for biosimilars in Ireland. It also requests feedback on prescriber-led switching and pharmacy-led substitution of biosimilars.

A survey of hospital specialists and pharmacists in Italy found that knowledge about biosimilars was lacking. The authors concluded that ‘educational interventions will be urgently required with the forthcoming approval of biosimilars under active development to avoid the risk of patients continuing to use more expensive drugs’.

In order to increase understanding and acceptance of biosimilars in Europe the EC published its improved biosimilar Q & A document for patients in January 2017. This was then expanded to be available in 23 languages in November 2017. Then in May 2017, the EC, in collaboration with EMA, issued an information guide on biosimilars for healthcare professionals, called ‘Biosimilars in the EU: Information guide for healthcare professionals’.

How to build trust in biosimilars was a subject highlighted at the Biosimilar Medicines Group (EBG)’s satellite symposium at the European Association of Hospital Pharmacists’ (EAHP) 2017 conference. Overall, emphasis by the speakers was on the need for increased education to improve trust in biosimilars, and the need for traceability of biosimilars [26].

Similarly, FDA launched its education campaign for biosimilars in October 2017. The educational materials include fact sheets and graphics for healthcare professionals, as well as materials for organizations to use in disseminating this information to their interested members.

More evidence is also being produced in support of the safety and efficacy of biosimilars. A study of biological disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) found no reason for physicians not to prescribe infliximab biosimilars. The evidence collected was then used to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of axSpA.

FDA Commissioner Dr Scott Gottlieb sees the current situation with biosimilars as being similar to that for generics 30 years ago. He says that ‘there is reluctance on the part of providers to switch over, certainly to switch patients off [of] therapy that they’re on, onto a biosimilar, or even to embrace a biosimilar, especially if you’re thinking about curative therapy’. However, despite the slow start, he sees ‘a lot of development activity’ and expects ‘to see a real pickup in the rate of biosimilar development’.

Given the high cost of biologicals the path for biosimilars to potentially provide much needed cost savings while still providing patients access to safe and efficacious treatments appears to be clear.

Moving forward

To summarize, a few of the key issues to be considered when it comes to biosimilar development include:

1. Increasing harmonization around the world is needed with respect to regulatory approval guidance for biosimilars.
2. Increasing harmonization around the world is also needed when it comes to how different countries or regions approach interchangeability of biosimilars.
3. The success of implementing switching to biosimilars will depend on a multi-stakeholder approach and needs to involve doctors, nurses, pharmacists and the procurement entity.
4. Increasing transparency and communication/education to patients about the efficacy/safety and benefits of biosimilars is required. Ensure greater patient involvement in decision-making processes. Patient confidence in biosimilars is key to acceptance and in many cases the nurse is the key point of contact for patient concerns and questions.
5. The traceability of biologicals remains an issue around the world and needs to be resolved/harmonized so that patients can easily be switched to different biological products, as there are post-swtich concerns that were not caused by the switch itself, the so-called ‘nocebo’ effect.
6. Government policies need to be introduced to support increased uptake of biosimilars.

Editor’s comment

It should be noted that ‘similar biologics’ approved in India, ‘non-originator biologicals’ approved in Russia or South Africa 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. 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 abstracted based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

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