Top developments in biosimilars during 2017

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

References
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2. U.S. Food and Drug Administration. Nonproprietary naming of biological products. Guidance for industry. January 2017 [homepage on the Internet]. [cited 2018 Feb 8]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf
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11. Claus BOM, Somers A, Bauters T. Pharmacovigilance of biosimilars and other biologicals within the hospital: current practices and future challenges. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(1):24-6. doi:10.5639/gabij.2017.0601.005
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19. Vogler S, Schneider P. Do pricing and usage-enhancing policies differ between biosimilars and generics? Findings from an international survey. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(2):79-88. doi:10.5639/gabij.2017.0602.015
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24. Generics and Biosimilars Initiative. First ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products 2017; 23 July 2017; Bangkok, Thailand. Available from: www.gabi-journal.net/about-gabi/educational-workshops/first-asean-educational-workshop-on-regulation-and-approval-of-biosimilarssimilar-biotherapeutic-products-2017
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Top developments in biosimilars during 2016

Submitted: 27 January 2017; Revised: 31 January 2017; Accepted: 1 February 2017; Published online first: 6 February 2017

Previous years have been momentous for biosimilars [1] and 2016 is no exception. This paper highlights the various developments that have taken place during 2016 for biosimilars. Important milestones achieved during 2016 were the biosimilar approvals of Inflectra (infliximab-dyyb), Erelzi (etanercept-szzs) and Amjevita (adalimumab-atto) by the US Food and Drug Administration (FDA).

FDA is also reviewing applications for Bioepis/Merck’s infliximab biosimilar candidate (SB2), Amgen/Allergan’s proposed bevacizumab biosimilar (ABP 215), Mylan/Biocon’s proposed trastuzumab biosimilar (Myl-1401O) and for the pegfilgrastim biosimilar candidate (CHS-1701) made by Coherus BioSciences. The agency, however, rejected an application from Sandoz for a pegfilgrastim biosimilar (LA-EP2006) in July 2016. FDA has also accepted an application for follow-on insulin glargine biological MK-1293 via the 505(b)(2) regulatory pathway, which allows FDA to reference previous findings of safety and efficacy for an already-approved product (Lantus), in addition to reviewing findings from studies of MK-1293.

In Europe, the etanercept biosimilar Benepali (SB4) and the infliximab biosimilar Flixabi were approved in January and May 2016, respectively. The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use also recommended approval of the teriparatide biosimilars Movymia and Terrosa, as well as the insulin glargine biosimilar Lusunda in November 2016. The agency is also currently reviewing biosimilar applications for adalimumab, bevacizumab, etanercept, insulin glargine, insulin lispro, pegfilgrastim, rituximab and trastuzumab.

In October 2016, US biotechnology company Biogen launched its infliximab biosimilar Flixabi in the UK.

In September 2016, Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) decided that the etanercept biosimilar Brenzys ‘could be marked as equivalent’ to the brand-name biological Enbrel (etanercept) on the Australian Pharmaceutical Benefits Scheme. The decision gives pharmacists the authority to substitute Brenzys for its reference product, Amgen/Pfizer’s arthritis blockbuster Enbrel (etanercept). The PBAC also endorsed switching between Enbrel and Brenzys, saying that ‘the drug, etanercept, is not immunogenic per se, and anti-drug antibodies are rare. Switching between brands of etanercept is unlikely to change this’.

In June 2016, Hospira, now part of Pfizer, announced that its infliximab biosimilar, Inflectra, had received approval from Canada’s medicines regulator, Health Canada, in three extra indications: Crohn’s disease, fistulising Crohn’s disease and ulcerative colitis. In September 2016, Merck Canada announced that it had received approval for its etanercept biosimilar Brenzys (SB4) from Health Canada – the first subcutaneous antitumour necrosis factor (anti-TNF) biosimilar available in Canada.

Elsewhere in South Korea, Samsung Bioepis launched its infliximab biosimilar, Renflexis, which received approval from the Korean Ministry of Food and Drug Safety (MFDS), in May 2016. The MFDS also approved Celltrion’s rituximab biosimilar (CT-P10), Truxima, in November 2016.

India-based biologicals specialist Biocon received Japanese regulatory approval for its biosimilar insulin glargine product in March 2016. Another biotech firm Kyowa Hakko Kirin announced in January 2016 that it had made a deal with Sandoz for exclusive marketing rights to Sandoz’s biosimilar rituximab in Japan.

Figure 1

Meanwhile, India’s drug regulator, the Drugs Controller General of India, granted marketing approval for bevacizumab ‘similar biologics’ from India-based generics makers Reliance Life Sciences and Hetero Group in June 2016. These approvals were followed by the launch of the products in August 2016.

Biologicals naming

The issue of naming for biologicals is a contentious one and this has not changed during 2016. Advocates for distinct names include the Biologics Prescribers Collaborative and the Alliance for Safe Biologic Medicines (ASBM). The Generic Pharmaceutical Association (GPhA), on the other hand, believes that different names could ‘erect barriers to patient access to new, more affordable medicines, and jeopardize their safety’. The Academy of Managed Care Pharmacy (AMCP) has also said that distinct names could result in ‘lower market adoption and cost-savings’ from biosimilars.

The World Health Organization (WHO) introduced the concept of a biological qualifier (BQ) for naming biologicals in 2014. This was followed by a draft proposal on naming biologicals, including biosimilars. In 2016, this has been followed by the proposal to proceed with a provisional implementation of the BQ scheme accompanied by a prospective impact study.

The International Generic and Biosimilar Medicines Association (IGBA) opposes the BQ. Although it says that it welcomes WHO’s continuous interest in the development of a global identification system for biologicals, the group stated that the ‘IGBA does not support the BQ proposal’. The IGBA added that ‘successful product identification and tracking using multiple identification components are already in force’.

FDA has proposed that all biologicals, including biosimilars, have non-proprietary names and that a four-letter meaningless suffix be added to the names to distinguish them from each other [2]. The agency issued final guidance detailing the agency’s requirements for the non-proprietary naming of biological products in January 2017. In its guidance FDA outlines how the ‘proper name’ of a biological will consist of a combination of the ‘core name’ and a distinguishable suffix, which will be ‘devoid of meaning’ and be ‘composed of four lowercase letters’. For example, the ‘proper name’ of products containing the fictitious core name biologicamab, could be biologicamab-cznm for the originator biological and biologicamab-hixf for the biosimilar.

Following the approval of the infliximab biosimilar Inflectra (infliximab-dyyb) by FDA, the American College of Rheumatology (ACR) issued a statement supporting the use of distinct names for biosimilars. The group stated that ‘the ACR supports distinct naming and transparent labelling for all biosimilar products to ensure correct prescribing and dispensing, post-marketing surveillance, prescriber confidence, and enhanced market uptake’. The ACR has also called on FDA to issue guidance on the substitution of biosimilars.

Studies of pharmacists, carried out by the AMCP and the Hematology/Oncology Pharmacy Association (HOPA) and the ASBM found that pharmacists had a preference for distinguishable names. However, the AMCP/HOPA study also found that using the same names for interchangeable biologicals would make pharmacists more likely to dispense biosimilars [3, 4].

State legislation on biosimilar substitution in the US

During 2016, additional state legislation was considered that would allow the substitution of biosimilars. Many of these proposed bills use compromise wording proposed by the GPhA in 2015. The latest states to consider or pass legislation allowing substitution of a biosimilar for an originator biological include Idaho, Kentucky, Michigan and Oregon.

Biosimilars guidance

FDA announced in the beginning of 2016 that it had finalized its guidance for industry on formal meetings between FDA and biosimilars sponsors. The agency also published draft guidance on biosimilars labelling and finalized guidance on clinical pharmacology data to support biosimilarity. Expected draft guidance on interchangeability did not materialize in 2016, but was finally published in January 2017.

In January 2016, EMA released a draft concept paper on the revision of the reflection paper on ‘Non-clinical and clinical development of interferon alfa biosimilars’. EMA is proposing to update the guidance based on experience gained with marketing authorization applications of reference products and scientific advice on biosimilar interferon alfa. The agency also introduced a new guideline on the monitoring of biologicals, including biosimilars in August 2016.

The Danish Ministry of Health, in partnership with the country’s regulatory agency (Laegemiddelstyrelsen), set up an action plan in 2016 to monitor biologicals and improve pharmacovigilance, as well as to improve understanding among healthcare professionals and patients.

Health Canada issued a new draft revised guidance document on the information and submission requirements for subsequent entry biologics (SEBs) in Canada. This update included new information on extrapolation of indications for SEBs [5].

In March 2016, India’s Central Drugs Standard Control Organization announced the release of proposed revised guidance for ‘similar biologics’ in India. These revised guidelines [6] will replace the original guidance issued in September 2012.

Finally, the Biosimilars Working Group (BWG) of the International Pharmaceutical Regulators Forum (IPRF) released a template for Public Assessment Summary Information for Biosimilar (PASIB). PASIB includes key information and summarized details of the biosimilar review and is expected to be of more use to countries that currently do not publish their reviews or do so only in a local language that is not English.

Clinical trials for biosimilars

Clinical trials have been a major feature of 2016, with numerous trials for biosimilars being carried out.

In February 2016, Epirus Biopharmaceuticals reported that it had started a phase III trial of its infliximab biosimilar (BOW015) in patients with active rheumatoid arthritis despite methotrexate therapy. In March 2016, Germany’s Merck KGaA reported that it had started a phase III clinical trial of its adalimumab biosimilar (MSB11022) in patients with chronic plaque psoriasis. In April 2016, South Korean electronics giant Samsung and biotechnology company Biogen Idec’s joint venture Samsung Bioepis started a phase III clinical trial of a biosimilar version (SB8) of Roche’s cancer blockbuster Avastin (bevacizumab).

In March 2016, researchers from Birmingham Children’s Hospital presented results from a study of the use of the infliximab biosimilar CT-P13 (Remsima/Inflectra) in children with inflammatory bowel disease. The results, according to the authors, showed that ‘the efficacy and safety of biosimilar infliximab (Inflectra) is comparable to the originator infliximab’.

US-based biologicals maker Sorrento Therapeutics (Sorrento) reported in May 2016 that its partner, MabTech, had successfully completed a combined phase II and III clinical trial in China for STI-004, a copy biological for omalizumab (Xolair). STI-004 met its primary endpoint in a multicentre, randomized, double-blind, placebo-controlled, clinical study. Meanwhile, phase III trials in China of cetuximab (STI-001) and infliximab (STI-002) copy biologicals from MabTech reportedly ‘met their primary endpoints in confirmatory, randomized, controlled, two-part phase III studies’.

In June 2016, generics giant Mylan and partner Biocon presented data from the companies’ phase III HERiTAge study of their biosimilar trastuzumab candidate, Myl-1401O. According to Mylan, the results of the double-blind, randomized, parallel group study confirmed the efficacy, safety and immunogenicity of Myl-1401O compared to Roche’s Herceptin (trastuzumab) both given in combination with paclitaxel as first-line therapy every three weeks in patients with HER2+ metastatic breast cancer. The companies submitted their marketing applications to EMA and FDA in August and November 2016, respectively.

In October 2016, Biocon and Mylan also presented results of a study comparing their biosimilar pegfilgrastim (MYL-1401H) to the originator (Neulasta), which, according to Mylan, ‘demonstrated equivalent efficacy’.

Samsung Bioepis also presented the results of studies of three of its biosimilars, Benepali (etanercept), Flixabi (infliximab) and candidate biosimilar SB5 (adalimumab) in June 2016. The data indicated ‘comparable outcomes with regards to both the efficacy and safety of treatment’ when compared to their respective reference products, according to the company.

US pharma giant Merck (also known as MSD outside the US) reported positive results in June 2016 from two phase III studies evaluating its insulin glargine biosimilar (MK-1293). In both studies, MK-1293 achieved its primary endpoint by demonstrating non-inferiority in change from baseline haemoglobin A1C (a measure of average blood glucose) and similar safety to Lantus (insulin glargine) after 24 weeks in patients with type 1 and type 2 diabetes.

Results of a study of Amgen and Allergen’s trastuzumab biosimilar (ABP 980) compared to Herceptin (trastuzumab), according to Amgen, ‘ruled out inferiority compared to trastuzumab but could not rule out superiority based on its primary efficacy endpoint of the difference of the percentage of patients with a pathologic complete response (pCR)’, which was defined by the absence of invasive tumour. Overall, adverse events and immunogenicity were also comparable between ABP 980 and Herceptin, according to the company [7].

US-based biosimilars developer Coherus BioSciences (Coherus) reported in July 2016 that follow-on results from a phase I study of its candidate pegfilgrastim biosimilar (CHS 1701) were positive.

Boehringer Ingelheim reported in November 2016 that new data from its phase I INVICTAN-1 study of its bevacizumab biosimilar, BI 695502, had ‘met all the pre-defined primary and secondary endpoints’. In addition, the results confirmed that BI 695502 was well tolerated, with no clinically relevant differences in safety or immunogenicity evaluations between the BI 695502 and bevacizumab treatment groups. They also have a phase III study (INVICTAN-2) underway to investigate the safety and efficacy of BI 695502 compared to Avastin in patients with advanced non-squamous non-small cell lung cancer.

Sandoz, which is the generics division of Novartis, reported in November 2016 the publication of the results of its EGALITY study in the British Journal of Dermatology. The confirmatory clinical safety and efficacy study shows, according to Sandoz, that its etanercept biosimilar (GP2015) ‘is equivalent to the originator biological, Enbrel (etanercept), in more than 500 adult patients over 52 weeks’.

Pharma giant Pfizer reported in November 2016 that its pivotal phase III REFLECTIONS B3271002 study of its trastuzumab biosimilar (PF-05280014) versus Herceptin (trastuzumab) had met its primary endpoint. The trial, according to Pfizer, ‘demonstrated equivalence in the primary endpoint of objective response rate (ORR) of PF-05280014 versus Herceptin, taken in combination with paclitaxel, in first-line patients with HER2+ metastatic breast cancer’. ORR is defined as the proportion of patients with tumour size reduction of a predefined amount and for a minimum period of time.

US-based biotechnology firm Momenta Pharmaceuticals (Momenta) reported on 29 November 2016 that the confirmatory phase III clinical study of its adalimumab biosimilar candidate (M923) developed in collaboration with Baxalta (now part of Shire) had met its primary endpoint. Momenta also said that ‘the estimated difference in responders was well within the pre-specified confidence interval, confirming equivalence’.

South Korean biotechnology company Celltrion reported in December 2016 that its pivotal phase III study ‘shows equivalence in pharmacokinetic and safety data between CT-P10 and reference rituximab’. Celltrion received approval from the MFDS for its rituximab biosimilar in November 2016. The company submitted its application for approval of CT-P10 to EMA in November 2015. Rival biosimilars maker Sandoz submitted the marketing application for its rituximab biosimilar to EMA for approval in May 2016.

A post-marketing study of the epoetin alfa biosimilar Retacrit claimed that the biosimilar is ‘effective and well tolerated in treating chemotherapy-induced anaemia’ [8]. And another two-year post-marketing study of the epoetin alfa biosimilar Binocrit claimed the biosimilar to be safe in daily clinical practice. The authors concluded that ‘the real-world safety profile of Binocrit, a biosimilar epoetin alfa, is consistent with the profile of originator epoetin alfa’ [9].

A study of biological-naïve patients with active rheumatoid arthritis reported that use of biosimilar rituximab resulted in prolonged benefit in the majority of patients and was well tolerated.

A study of originator biological and biosimilar erythropoiesis-stimulating agents (ESAs) in Northern Italy reported no difference in the effects on haemoglobinemia after the first three months of treatment when using a comparable dose. The results, according to the authors, ‘suggest that the lowest-cost ESA should be prescribed in chronic kidney disease/cancer patients, irrespective of ESA type’ [10].

A study of tumour necrosis factor inhibitors carried out by international authority on health improvement the John Hopkins Bloomberg School of Public Health suggests that biosimilars are just as good as their reference compounds [11].

Authors from the Versilia and Manzoni Hospitals in Italy reported the case of a patient who developed pure red cell aplasia (PRCA) following subcutaneous administration of epoetin zeta, which is one of the two biosimilars of epoetin alfa licensed in Europe. The authors believe this to be the first PRCA case related to epoetin zeta [12].

Separately, researchers from the University of Massachusetts, USA and Newcastle University in the UK argued that clinical trial design should be standardized for future studies of biosimilars. Indeed, they argued that a ‘standard clinical trial design be adopted for all biosimilars of a particular [originator biological] in a given disease’ [13].

Extrapolation

Extrapolation of indications was once again a topic of interest during 2016 [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.

The BWG of IPRF released a draft reflection paper on the extrapolation of indications in the authorization of biosimilars in September 2016. The draft reflection paper suggests that authorization of biosimilars be carried out using a stepwise approach. Where the reference product has more than one therapeutic indication the group proposes that, once comparability has been demonstrated in one indication, ‘extrapolation of clinical data to other indications of the reference product could be acceptable’.

Switching

Switching patients from originator biologicals to biosimilars can be a contentious issue and was also a topic of interest during 2016. The British Society of Gastroenterology released guidance in February 2016 recommending that stable patients be switched to biosimilar infliximab (CT-P13). In March 2016, South Korean biologicals specialist Celltrion presented results of real-world studies supporting the safety and efficacy of switching to biosimilar infliximab.

In February 2016, the Portuguese National Authority of Medicines and Health Products (INFARMED, IP) released a Portuguese position paper on the use of biosimilars in psoriasis. In their recommendation document, although they welcomed biosimilars in the treatment of psoriasis and psoriatic arthritis, they also stated that ‘there is no evidence to support switching between a reference biological and a biosimilar and vice-versa, so this should not be recommended’.

In March 2016, researchers from Spain presented results from a study on the use of the infliximab biosimilar Remsima in ulcerative colitis disease patients in clinical practice after six months treatment. The authors concluded that ‘Remsima is safe’, stating that ‘most of the patients with ulcerative colitis who switched from Remicade to Remsima continue in remission after six months of treatment’. They did concede, however, that the follow-up was short and that there was no control group, highlighting the need for further studies.

In October 2016, data presented for the NOR-SWITCH study showed that the group of patients that were switched to biosimilar infliximab, Remsima (CT-P13), had comparable efficacy and safety to those who remained on the originator biological. The study, which was sponsored by the Norwegian Government and included nearly 500 patients at 40 sites across Norway, concluded that ‘biosimilar infliximab was not inferior to the originator’.

However, in contrast, a study of antibodies to infliximab, comparing both the originator (Remicade) and biosimilar (Inflectra/Remsima; CT-P13) versions, has shown ‘cross-immunogenicity’ between the originator and biosimilar in patients with rheumatic diseases. This study therefore suggests that ‘switching may not be suitable for patients with immunogenicity’ [16].

A study from Italy also found that switching is not limited to reference products and their biosimilars, but also often occurs between originator biologicals and other originator biologicals within the same category [17].

Recently, in January 2017, FDA issued its much anticipated guidance on the interchangeability of biosimilars with their reference biologicals in order to claim ‘interchangeability’ for the biosimilar, additional information must be submitted that shows that the biological product ‘can be expected to produce the same clinical result as the reference product in any given patient’ and that ‘for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.’ Switching studies, FDA states, ‘should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product’.

Labelling and reimbursement

In the US, the GPhA has raised concerns over the Centers for Medicare and Medicaid Services (CMS) biosimilars reimbursement policy. The GPhA believes that the proposed rule (CMS-1631-P) ‘unfairly disadvantages non-interchangeable biosimilars’ and will ‘erode the economic incentives that drive the US healthcare system to lower-cost therapeutic alternatives’, especially for biosimilars.

The GPhA and the Biosimilars Council have also expressed concern over a requirement in FDA’s draft guidance on biosimilar labelling to include a statement on biosimilarity. The groups believe that ‘the proposed biosimilarity statement may be confusing’ and ‘is at best unnecessary’. They go on to say that ‘the FDA has never required any similar statement for products found to be therapeutically equivalent, and has not provided sufficient justification for its inclusion in biosimilar labelling’.

Meanwhile, a survey carried out by EuropaBio found that doctors in Europe want more details in biosimilars labelling. Their survey found that the Summary of Product Characteristics was the third most often referenced source of information when prescribing a biological product, including a biosimilar, after peer-reviewed journals (92.4%) and professional guidelines (91.5%). It also found that most physicians preferred modified label samples that included additional information about what data had been generated with which product.

Biosimilars collaborations

Biosimilars deals were also popular during 2016. Mylan agreed an exclusive global collaboration with Momenta to develop, manufacture and commercialize six of Momenta’s biosimilar candidates. Included in the six is a version of Bristol-Myers Squibb’s rheumatoid arthritis drug, Orencia (abatacept), however, the other five biosimilars were not specified.

In March 2016, US biotechnology company Oncobiologics and healthcare performance improvement alliance Premier announced that they had entered into a collaboration aimed at increasing the use of biosimilars.

Contract solutions provider SGS announced in March 2016 that it had entered into collaboration with innovative life science company DiscoverX to provide simple and qualified assays for functional comparability, for use in quality control, lot release and stability testing of biosimilars and biobetters.

Indian generics maker Cipla announced a deal to set up South Africa’s first biosimilars manufacturing facility. According to Cipla, the state-of-the-art manufacturing site means the creation of Africa’s first ‘bio-cluster’ and will attract world-class research efforts. Construction will begin in early 2017, with full operations expected by the third quarter of 2018.

Japan-based Fuji Pharma and Chong Kun Dang Pharmaceutical (CKD Pharma) made a biosimilars deal for Fuji Pharma to have the exclusive rights in Japan for the development, manufacture, distribution and sale of CKD Pharma’s darbepoetin alfa biosimilar (CKD-11101). Separately, US-based biologicals specialist Amgen and Japan-based Daiichi Sankyo announced in July 2016 that they had made an exclusive agreement to commercialize nine biosimilars in Japan. In fact, Japan is proving to be a favourable market for biosimilars. Uptake of biosimilars in Japan is on a par with generics use for some products, making Japan an attractive market for biosimilars makers.

Other biosimilar collaborations made during 2016 included deals between PlantForm and Guelph University for biosimilar trastuzumab, between Lannett and Chinese partner YiChang HEC ChangJiang Pharmaceutica (YiChang) for biosimilar insulin and between Hungary-based Gedeon Richter (Richter) and South Korea-based biologicals specialist DM Bio for biosimilar trastuzumab.

General issues

The increasing number of clinical trials being carried out for biosimilars in 2016, the number of global biosimilar approvals, as well as further FDA approvals and the growing number of biosimilar applications in the US, all suggest that the future for biosimilars is a bright one.

An analysis carried out by the RAND Corporation highlighted the cost-savings to be made and therefore the need for biosimilars. The report concluded that introducing biosimilars of complex biologicals used to treat illnesses, such as cancer and rheumatoid arthritis, could cut spending on biologicals in the US by US$44 billion over the next decade. Furthermore, if countries can negotiate discounts such as those seen in Norway (47–75%) [18] and France (45%), the savings could be even larger.

Biosimilars penetration in Europe still varies widely between different countries. Penetration of biosimilars varies from a low of 0% for HGH in countries such as Belgium and Ireland to an incredible high of 100% for granulocyte-colony stimulating factor in Croatia. In fact, Eastern Europe is leading the way in biosimilars penetration, perhaps driven by economic factors.

One reason for such differences in Europe could be the gap between the regulatory decisions that govern biosimilar approval and the recommendations of medical societies. The fact that the views of medical societies, whose members are the physicians that will prescribe biosimilars, disagree with those of regulators threatens to hold back biosimilar uptake. The problem could be resolved, however, by clinicians and regulators exchanging more information [19].

Another issue is thought to be education regarding biosimilars. A survey of doctors carried out by SERMO, a global social media network, found that half of doctors do not feel that they have enough educational information to prescribe biosimilars to their patients.

To try and address this, in February 2016 the Biosimilars Forum launched a new biosimilars education initiative. The ‘Partnership for Biosimilars Education and Access’ focuses on raising awareness and encouraging access to biosimilars in the US. FDA has also highlighted trust and education as critical factors in ensuring patient access to biosimilars. As part of its ongoing mission to educate industry, the public and healthcare professionals about biosimilars, FDA released its online educational course for healthcare professionals: ‘FDA Overview of Biosimilar Products’. In addition, Merck launched its Biosimilars Clarified (www.merckclarifiesbiosimilars.com), an online resource intended to be used as an educational platform for patients, caregivers and the healthcare community.

In Europe, Medicines for Europe (previously the European Generic and Biosimilar Medicines Association) released its Biosimilars Handbook in February 2016. The handbook describes both the science and technology behind biosimilars, as well as how they are produced and regulated. It is intended to be a reference source for, among others, patients, patient advocacy groups, pharmacists, physicians and prescribers, as well as for payers, politicians and policymakers.

In April 2016, the British Generic Manufacturers Association launched its expert sector group on biosimilars, the British Biosimilars Association. The group is exclusively focused on biosimilars and its main focus will be to try and improve access to biosimilars thus ensuring that patients in the UK can benefit from these life-saving and life-changing medicines to the same extent as those elsewhere in Europe. Currently, the UK lags behind some European countries in the use of biosimilars. A report released in 2016 found that if biosimilar adoption was increased they could halve the cost of treatment in the UK. The UK’s healthcare cost watchdog NICE (National Institute for Health and Care Excellence) recommended in January 2016 that rheumatoid arthritis patients indicated for treatment with biologicals should ‘start treatment with the least expensive drug’.

Although it is hard to predict where the evolving biosimilars market will lead, given the high cost of biologicals it is clear that biosimilars have the potential to lead to much needed cost savings while still providing patients access to safe and efficacious treatments.

Editor’s comment

It should be noted that ‘follow-on biologicals’ approved in Brazil, ‘copy biologicals’ approved in China, ‘similar biologics’ approved in India, ‘biocomparables’ approved in Mexico, and ‘bioterapéuticos similares’ approved in Venezuela 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 based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

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The anti-TNF biosimilar CT-P13 had comparable efficacy to infliximab in rheumatoid arthritis over one year

Submitted: 24 May 2016; Revised: 8 June 2016; Accepted: 10 June 2016; Published online first: 24 June 2016

The introduction of biologicals has revolutionized the treatment of immune-mediated diseases such as rheumatoid arthritis (RA) [1]. However, in many countries, patient access to these agents is restricted due to their high costs [2, 3]. Biosimilar drugs offer a potential solution to this problem, with such drugs generally proving to be cheaper than the corresponding biological reference products (RPs).

Infliximab is an anti-tumour necrosis factor (TNF) monoclonal antibody that is widely used in the treatment of RA and other immune-mediated diseases [4]. A biosimilar of infliximab RP called CT-P13, also known as Remsima or Inflectra, is now approved in Europe, the US and elsewhere for use in all indications for which the RP (Remicade) is licensed, including RA. As recently reported in the journal Arthritis Research & Therapy, the phase III clinical trial PLANETRA has provided important data that supported these regulatory approvals of CT-P13 [5].

PLANETRA enrolled 606 patients with RA from 19 different countries who were then randomized to receive either CT-P13 or the RP for up to 54 weeks. Clinical efficacy was assessed via American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates. Disease activity was measured using a variety of different measurements, including Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and European League Against Rheumatism (EULAR) responses. Patient-reported outcomes (PROs), pharmacokinetics (PK) and safety were also assessed [5].

The clinical efficacy of CT-P13 and the RP over the 54-week study was comparable, with similar ACR20, ACR50 and ACR70 responses obtained throughout the course of the study and at completion, see Figure 1. DAS28, SDAI and CDAI scores all decreased over time, with similar reductions observed for CT-P13 and the RP. Likewise, the proportion of patients reporting a good or moderate EULAR response was comparable for both treatments throughout the study. All PROs had improved from baseline by week 14 and improvements were maintained in both treatment groups for the remainder of the study period. No significant differences in immunogenicity, safety or PK were detectable between CT-P13 and the RP [5].

Figure 1
The results of PLANETRA reported that CT-P13 is comparable to the RP in the treatment of RA for up to 54 weeks, in terms of efficacy, PK and safety [5]. An extension study which ran up to 102 weeks also showed that the efficacy and safety of treatment were unaffected when patients previously treated with the RP were switched to CT-P13 [6].

The size of the biosimilar market is set to increase rapidly over the coming years as more and more biologicals come to the end of their patent terms. An increasing number of countries recommend using the least expensive drug to treat conditions such as RA, and biosimilars are typically offered at a lower price than their RPs. Therefore, clinical studies such as PLANETRA will become increasingly important in guiding clinical decision-making in order to reduce healthcare costs and increase patient access to biological therapies.

Competing interests: The authors of the research papers [5, 6] declared that DHY and WP are consultants for Celltrion. For full details of all authors’ conflicts of interest, see the research papers [5, 6].

Provenance and peer review: Article abstracted based on published scientific or research papers [5, 6]; internally peer reviewed.

Editorial support for the article abstract of Professors Won Park and Dae Hyun Yoo was provided by Philippa Flemming, PhD, funded by Celltrion Healthcare Co Ltd.

References
1. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861-74.
2. Nast A, Mrowietz U, Kragballe K, et al. Barriers to the prescription of systemic therapies for moderate-to-severe psoriasis – a multinational cross-sectional study. Arch Dermatol Res. 2013;305(10):899-907.
3. Putrik P, Ramiro S, Kvien TK, et al. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. 2014;73(1):198-206.
4. Hsia EC, Ruley KM, Rahman MU. Infliximab (Remicade®): from bench to clinical practice. A paradigm shift in rheumatology practice. Int J Rheum Dis. 2006;9(2):107-18.
5. Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther. 2016;18:82. doi:10.1186/s13075-016-0981-6
6. Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. doi:10.1136/annrheumdis-2015-208786

Disclosure of Conflict of Interest Statement is available upon request.

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Switching from the infliximab reference product to CT-P13 in patients with rheumatoid arthritis or ankylosing spondylitis: results of the PLANETAS and PLANETRA extension studies

Submitted: 24 May 2016; Revised: 8 June 2016; Accepted: 10 June 2016; Published online first: 24 June 2016

CT-P13, also known by its brand names Remsima or Inflectra, is a biosimilar of the infliximab reference product (RP) Remicade. CT-P13 is approved in Europe, the US and elsewhere for use in all indications for which the RP is licensed, including rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Approval of CT-P13 was partly based on findings from two pivotal clinical trials – PLANETAS and PLANETRA – which concluded that CT-P13 and the RP were highly comparable in terms of pharmacokinetics, efficacy, immunogenicity and safety in AS patients (PLANETAS) and RA patients (PLANETRA). Recently, data from extension phases of the original two clinical trials have been published in Annals of the Rheumatic Diseases. The data reported that it was possible to switch from the RP to CT-P13 without any detrimental effects on safety or efficacy. The studies also reported that CT-P13 was well tolerated and effective for up to two years in patients with RA and AS [1, 2].

Following the main 54-week randomized controlled trials during which patients with AS or RA received either the RP or CT-P13 [3, 4], patients were invited to enrol into 48-week extension studies. All patients who enrolled onto the extension studies were treated with CT-P13. Clinical efficacy and disease activity were assessed using a variety of different measurements, including Assessment of SpondyloArthritis international Society (ASAS) response rates (in patients with AS) and American College of Rheumatology (ACR) response rates (in patients with RA).

Three hundred and two patients with RA were enrolled and 301 were treated with CT-P13 in the PLANETRA extension study. Of these, 158 had received CT-P13 in the original study (‘maintenance group’) and 144 had received the RP (‘switch group’). One hundred and seventy-four patients with AS were treated in the PLANETAS extension study. Of these, 88 had received CT-P13 in the original study (‘maintenance group’) and 86 had received the RP (‘switch group’).

In both extension studies, clinical efficacy was similar in patients in the maintenance and switch groups. In RA patients, ACR20, ACR50 and ACR70 rates were not different between the maintenance and switch groups, see Figure 1. In AS patients, ASAS20, ASAS40 and ASAS partial remission rates were also similar between the two groups, see Figure 2.

Figure 1

Figure 2
Clinical efficacy was maintained over 2 years in the patients with RA and AS who had received CT-P13 during both the original and extension studies. In patients with RA, the ACR20 response rate was 77.0% after 1 year of treatment with CT-P13, and 71.7% after 2 years of treatment. In patients with AS, the ASAS20 response rate was 70.5% after 1 year of treatment with CT-P13, and 80.7% after 2 years of treatment.

CT-P13 was well-tolerated during both extension studies, with a safety profile that was consistent with that of the RP [5, 6]. The proportion of patients developing anti-drug antibodies was also similar in the maintenance and switch groups in either extension study.

As patent expiration dates loom for many biological drugs, there is increasing interest in the development of biosimilar drugs. With tight healthcare budgets, many countries commonly recommend the least expensive drug be used for treating conditions such as RA and AS [7, 8]. With biosimilars typically being less expensive than originator biologicals [9], studies that examine whether patients can be switched from the originator biological to a biosimilar are vital to aid clinical decision-making. Switching to the biosimilar may lead to cost savings and increased access to treatment for more patients with these debilitating diseases.

Competing interests: The authors of research papers [1, 2] declared that DHY and WP are consultants for Celltrion; for full details of all authors’ conflicts of interest, see the research papers [1, 2].

Provenance and peer review: Article abstracted based on published scientific or research papers [1, 2]; internally peer reviewed.

Editorial support for the article abstract of Professors Won Park and Dae Hyun Yoo was provided by Philippa Flemming, PhD, funded by Celltrion Healthcare Co Ltd.

References
1. Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. doi:10.1136/annrheumdis-2015-208786
2. Park W, Yoo DH, Miranda P, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitits: 102-week data from the PLANETAS extension study. Ann Rheum Dis. doi:10.1136/annrheumdis-2015-208783. Epub ahead of print
3. Yoo DH, Racewicz A, Brzwzicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther. 2016;18:82. doi:10.1186/s13075-016-0981-6
4. Park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther. 2016;18:25.
5. Braun J, Deodhar A, Dijkmans B, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period. Arthritis Rheum. 2008;59(9):1270-8.
6. Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50(4):1051-65.
7. National Institute for Health and Care Excellence. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. NICE technology appraisal guidance (TA375). 26 January 2016 [homepage on the Internet]. [cited 2016 Jun 8]. Available from: https://www.nice.org.uk/guidance/TA375/chapter/1-Recommendations.
8. National Institute for Health and Care Excellence. TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis. NICE technology appraisal guidance (TA383). 01 February 2016 [homepage on the Internet]. [cited 2016 Jun 8]. Available from: https://www.nice.org.uk/guidance/ta383.
9. IMS Health. Shaping the biosimilars opportunity: a global perspective on the evolving biosimilars landscape. December 2011 [homepage on the Internet]. [cited 2016 Jun 8]. Available from: http://weinberggroup.com/pdfs/Shaping_the_biosimiliars_opportunity_A_global_perspective_on_the_evolving_biosimiliars_landscape.pdf

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


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Top developments in biosimilars during 2015

Submitted: 14 January 2016; Revised: 26 January 2016; Accepted: 27 January 2016; Published online first: 9 February 2016

Once again the biosimilars industry has had a busy year [1]. Perhaps the most important milestone achieved during 2015 was the landmark decision made by the US Food and Drug Administration (FDA) on 6 March 2015 to approve Sandoz’s filgrastim biosimilar, Zarxio (filgrastim-sndz), for all five indications of the originator product (Neupogen).

FDA is also reviewing applications for Hospira’s epoetin alfa biosimilar (Retacrit), Celltrion’s infliximab biosimilar candidate (CT-P13), Sandoz’s etanercept biosimilar (GP2015), and Apotex’s filgrastim (Grastofil) and pegfilgrastim biosimilars.

The Centers for Medicare & Medicaid Services (CMS), which provides health insurance for the elderly and children in the US, issued three biosimilar reimbursement documents in April 2015. The documents cover Medicare Part B, Part D and Medicaid and aim to remove incentives from physicians to prescribe more costly brand-name originator biologicals rather than biosimilars.

In Europe, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of Benepali (SB4) in November 2015. The drug is an etanercept biosimilar produced by Samsung Bioepis, which is a joint venture between South Korean electronics giant Samsung and biotechnology company Biogen. The agency is also currently reviewing biosimilar applications for enoxaparin sodium, etanercept, infliximab, pegfilgrastim and rituximab.

In February 2015, injectable generics specialist and biosimilars maker Hospira launched its infliximab biosimilar, Inflectra, in several major European markets. This increased the number of European countries Inflectra is marketed in to 24 and nearly doubled its presence across Europe. This was followed by the launch of Accofil (filgrastim), which is generics company Accord Healthcare’s first biosimilar approved in Europe. In March 2015, Mundipharma launched Remsima (infliximab biosimilar) in several major markets, including Germany and The Netherlands.

In May 2015, Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of Eli Lilly’s biosimilar insulin glargine, Basaglar, in the country’s Pharmaceutical Benefits Scheme (PBS). Basaglar is the first biosimilar insulin to be approved in Australia. Australia’s PBAC has also recommended that biosimilars are suitable for substitution at the pharmacy level. Meanwhile, Australia’s drug regulator, the Therapeutic Goods Administration (TGA), approved Hospira’s infliximab biosimilar Inflectra in August 2015.

In March 2015, Hospira launched its infliximab subsequent entry biological (SEB) Inflectra in Canada, the country’s first SEB monoclonal antibody therapy.

Elsewhere, the Korean Ministry of Food and Drug Safety (MFDS, formerly the Korea Food and Drug Administration) approved the infliximab biosimilar Renflexis on 4 December 2015 and the etanercept biosimilar Brenzys in September 2015, both from Samsung Bioepis.

Partners Eli Lilly and Boehringer Ingelheim received Japanese regulatory approval for their biosimilar insulin glargine product (LY2963016) in January 2015.

In May 2015, Iran’s National Regulatory Authority, the Food and Drug Organization (FDO), approved its first rituximab biogeneric (Zytux). The medicine received its marketing authorization based on the previously published national guideline for marketing of biogenerics in Iran.

Russia’s Ministry of Health Fig 1 approved Celltrion’s non-originator biological infliximab, Remsima, in July 2015.

Brazil’s medicines agency, the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, ANVISA), announced in April 2015 that it had approved its first follow-on biological medicine Remsima (infliximab) through its ‘development by comparability’ pathway. The Venezuelan medicines agency, the Instituto Nacional de Higiene ‘Rafael Rangel’ (INHRR National ‘Rafael Rangel’ Institute of Hygiene) also approved Celltrion’s infliximab bioterapéuticos similares in April 2015.

Meanwhile, India’s drug regulator, the Drugs Controller General of India (DCGI), granted marketing approval for a rituximab ‘similar biologic’ from Reliance Life Sciences in February 2015. Indian drugmaker Intas Pharmaceuticals (Intas) launched its ‘similar biologic’ of etanercept (Intacept) in India in March 2015. Intas then launched its ranibizumab similar biologic, Razumab, in June 2015. India-based generics maker Hetero Group launched a similar biologic of rituximab, Maball, in August 2015.

Biosimilars naming

The contentious issue of how to name biosimilars was once again a hot topic for discussion during 2015 [2]. According to the World Health Organization, almost half of the comments on its proposed biological qualifier (BQ) for naming biologicals were positive. WHO published a draft policy ‘Biological Qualifier – an INN proposal’ proposing a possible four-letter alphabetic code for all biologicals in July 2014. The Generic Pharmaceutical Association (GPhA), however, argued that ‘INN [International Nonproprietary Name] naming has been simple and intuitive and this should not be changed’, stating that the brand name is the distinguishing factor. Hospira also argued that ‘it is essential for biosimilar drugs to be given the same non-proprietary names as original biologic[al]s to ensure that patients receive the full benefit of greater access and lower costs that these medicines can bring.’

On the other hand, the American College of Rheumatology (ACR) has stated that ‘biosimilars must have distinct names allowing them to be distinguished from each other and their reference products’. This, the ACR states, ‘is essential for ongoing pharmacovigilance’. The ACR also believes that ‘the decision to substitute a biosimilar should only be made by the prescriber’ and ‘objects to compulsory switching of stable patients to a different medication (including a biosimilar)’.

FDA has also proposed that all biologicals and biosimilars have non-proprietary names and that a four-letter suffix be added to the names to distinguish them from each other. Biosimilars makers, however, would prefer to use the same non-proprietary names as the brand-name biologicals without any suffix, while originator manufacturers would prefer completely different names. Others, however, are concerned that using a ‘suffix deliberately designed to be “devoid of meaning” creates an unnecessary barrier to the use of distinguishable suffixes’.

Results of a survey carried out by the Alliance for Safe Biologic Medicines (ASBM) showed that 90% of physicians thought that it was important that a product label for a biosimilar clearly indicates that it is a biosimilar.

Australia’s drug regulatory agency, TGA is also reviewing its plans for naming biosimilars, ‘following recent international developments in the area of biosimilar naming’. The agency had previously proposed that all biosimilars in Australia have distinguishable names.

Substitution of biosimilars for originator biologicals can also be a contentious issue. However, according to a survey carried out in US pharmacists, most (75%) would be confident in substituting an interchangeable biosimilar with the reference product if both shared the same active ingredient or non-proprietary name of the reference biological.

The Sociedade Portuguesa de Reumatologia (Portuguese Society of Rheumatology) advised in its position statement that biosimilars should have a different INN or be prescribed by brand name. The society also recommended that automatic substitution of originators by biosimilars should not be allowed.

State legislation in the US

In January 2015, biologicals companies including Amgen, Actavis, Sandoz, Hospira and Genentech; and the GPhA agreed to support compromise automatic substitution legislation that would allow interchangeable biologicals to be automatically substituted at the pharmacy. Critical points are that the wording does not specify the notification period, and that the communication is to be done via the use of an electronic system where possible – thus reducing any delays for patients and reducing the burden on pharmacists.

During 2015 additional state legislation has been considered that would allow the substitution of biosimilars [3]. Many of these proposed bills use the compromise wording proposed by the GPhA. The latest states to consider or pass legislation allowing substitution of a biosimilar for an originator biological include California, Colorado, Georgia, Idaho, Illinois, Maryland, Massachusetts, New Jersey, North Carolina, Tennessee, Texas, Utah and Washington.

On 18 June 2015, US lawmakers Steve Stivers and Peter Welch reintroduced the Fair Access for Safe and Timely (FAST) Generics Act to increase consumer access to generics, boost market competition and ultimately save consumers money.

Guidance and recommendations

FDA issued four final biosimilars guidance documents in 2015. These included one on questions and answers about the biosimilars pathway, one on formal meetings between FDA and biosimilars sponsors, one on quality considerations in demonstrating biosimilarity, and one on scientific considerations in demonstrating biosimilarity. The agency also published a draft guidance document addressing additional questions and answers, which includes a question on the issue of interchangeability with reference biologicals.

In January 2015, FDA also asked drugmakers to comment on the information requirements for biosimilars interchangeability.

EMA released its finalized guideline on the non-clinical and clinical development of insulin biosimilars in March 2015. The new guideline lays down the non-clinical and clinical requirements for recombinant insulin-containing biosimilars, including human insulin and insulin analogues (both referred to as insulin). The final guideline, however, rejected requests to accept batches of reference (approved) biological products sourced from outside the European Economic Area (EEA), as is now possible for other biosimilars.

The TGA announced on 10 April 2015 that it was carrying out public consultations on the adoption of two European Union (EU) guidelines (the overarching biosimilars guideline and the guideline on non-clinical and clinical issues) in Australia. The TGA has already adopted many of EMA’s guidelines for biosimilars, as well as publishing its own guidance on the evaluation of biosimilars.

The Dutch Medicines Evaluation Board (MEB) updated its position on biosimilars, stating that ‘biosimilars have been proven to have no relevant differences compared to an innovator biological medicinal product as far as quality, safety and efficacy are concerned’.

In May 2015, the Finnish Medicines Agency, Fimea, announced that it was recommending the interchangeability of biosimilars for their reference biologicals. The Fimea recommendation does not, however, recommend automatic substitution at the pharmacy level. The agency specifically recommends that biosimilars are interchangeable with their reference products only under the supervision of a healthcare professional.

Following increasing interest in biosimilars in Canada, the Canadian Generic Pharmaceutical Association (CGPA), which represents Canada’s generics industry, set up a new CGPA Biosimilars Board in April 2015. Canada’s federal department responsible for health, Health Canada, has thus far approved three SEBs for use in Canada. Similarly, in the US, the US Generic Pharmaceutical Association (GPhA) launched its Biosimilars Council, which aims to be an educational resource for the general public and patient groups seeking information about the safety and effectiveness of biosimilars.

In March 2015, the Mexican regulatory body for approval of medicines, the Federal Commission for the Protection against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios, COFEPRIS), issued rules for older non-originator biologicals registered prior to 19 October 2011, when the country’s guidelines for ‘biocomparables’ were first published, mandating that companies conduct clinical trials to prove biosimilarity.

Clinical trials for biosimilars

In October 2015, Baxalta – a spinoff company from Baxter International – and US-based biotechnology firm Momenta Pharmaceuticals (Momenta) started a phase III clinical trial for their adalimumab biosimilar (M923) in patients with chronic plaque psoriasis. Meanwhile, in The Netherlands another study into the effects of switching patients from originator infliximab to biosimilar infliximab was initiated.

In February 2015, US biopharmaceutical giant Amgen announced positive results from its phase III clinical trial for its adalimumab biosimilar (ABP 501) in patients suffering from rheumatoid arthritis. The company is also carrying out a phase III clinical trial of its biosimilar adalimumab in patients suffering from plaque psoriasis.

Phase III trials of etanercept biosimilar SB4 and infliximab biosimilar SB2 from Merck and Samsung Bioepis reportedly ‘met their primary endpoints, demonstrating equivalence’ to the originator biological in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy.

A study of adverse drug reactions reported in Italy showed no relevant difference between the number and type of side effects reported for biosimilars and their corresponding originators, according to researchers from the Clinical Pharmacology Unit at the University of Messina, Italy.

Results of clinical experience with Celltrion’s infliximab biosimilar Remsima (CT-P13) reportedly show comparable safety and efficacy in inflammatory bowel disease patients.

Results of a post-marketing clinical study of infliximab biosimilar Inflectra claim that the biosimilar has equivalent effectiveness compared to the originator biological (Remicade) in patients with rheumatoid arthritis and ankylosing spondylitis when switched from Remicade.

A study of the treatment of patients with chronic kidney disease undergoing haemodialysis with ‘biocomparable’ and originator erythropoietin in Mexico reportedly showed comparable efficacy and safety in terms of changes in haemoglobin levels.

A retrospective analysis of cancer patients who received either originator or ‘similar biologic’ rituximab chemotherapy showed comparable efficacy and safety, according to a study by researchers from the Tata Memorial Centre, Mumbai, India.

Extrapolation

Extrapolation of indications was also a topic discussed during 2015 [46]. 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.

The Spanish Society of Rheumatology (Sociedad Española de Reumatología, SER) in its position statement on biosimilars agrees that ‘extrapolation of indications must be justified by the standards of the EMA’, but adds that ‘if necessary’ this should be ‘individually proven via double-blind randomized clinical trials that directly compare the biosimilar with the reference drug’. Paediatricians from Europe are also concerned about extrapolation of the limited amount of available clinical data from adults with rheumatologic diseases to children with inflammatory bowel disease.

Biosimilars collaborations

Biosimilar deals were also popular during 2015. US-based injectables specialist Hospira and US biotechnology firm Pfenex announced in February 2015 that they had entered into an agreement to exclusively develop and commercialize PF582 (ranibizumab), Pfenex’s leading biosimilar candidate. US-based Epirus Biopharmaceuticals (Epirus) announced in May 2015 that it had made a deal with biosimilars specialist mAbxience for distribution of BOW015 (infliximab) in Latin America.

Other biosimilar collaborations made during 2015 included deals between Cipla and Mabpharm, Strides Arcolab and Oncobiologics, and NeuClone and the Serum Institute.

The future

The increasing number of clinical trials being carried out for biosimilars in 2015, the number of global biosimilar approvals, the first FDA approval and the growing number of biosimilar applications in the US, all suggest that the future for biosimilars is a bright one.

An analysis carried out by the RAND Corporation highlights the cost-savings to be made and therefore the need for biosimilars. The report finds that introducing biosimilars of complex biologicals used to treat illnesses, such as cancer and rheumatoid arthritis, could cut spending on biologicals in the US by US$44 billion over the next decade. Furthermore, if countries can negotiate discounts, such as those seen in Norway (75%) [7] and France (45%), the savings could be even larger.

Biosimilars penetration in Europe still varies widely between different countries. Penetration of biosimilars varies from a low of 0% for human growth hormone (HGH) in countries such as Belgium and Ireland to an incredible high of 100% for granulocyte colony-stimulating factor (G-CSF) in Croatia. In fact, Eastern Europe is leading the way in biosimilars penetration, perhaps driven by economic factors.

Editor’s comment

It should be noted that ‘similar biologics’ approved in India, ‘follow-on biologicals’ approved in Brazil, ‘biocomparables’, approved in Mexico and ‘bioterapéuticos similares’ approved in Venezuela might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The European Medicines Agency’s 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.

Source: GaBI Online

Competing interests: None.

Provenance and peer review: Article prepared based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. Derbyshire M. Top developments in biosimilars during 2014. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):42-7. doi:10.5639/gabij.2015.0401.010
2. Robertson JS. The challenges of nomenclature – INN, biosimilars and biological qualifiers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):110-2. doi:10.5639/gabij.2015.0403.025
3. Derbyshire M. Update on US state legislation on biosimilars substitution.
Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):95-7. doi:10.5639/gabij.2015.0402.020
4. Perks B. Supporting biosimilarity and extrapolation. Generics and Biosimilars
Initiative Journal (GaBI Journal). 2015;4(4):180-4. doi:10.5639/gabij.2015.0404.041
5. Derbyshire M. European biosimilars conference highlights extrapolation as key
issue. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):149-50. doi:10.5639/gabij.2015.0403.032
6. Gerrard TL, Johnston G, Gaugh DR. Biosimilars: extrapolation of clinical use to
other indications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):118-24. doi:10.5639/gabij.2015.0403.027
7. Mack A. Norway, biosimilars in different funding systems. What works?. Generics
and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):90-2. doi:10.5639/gabij.2015.0403.027

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


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Top developments in biosimilars during 2014

Submitted: 10 February 2015; Revised: 24 February 2015; Accepted: 25 February 2015; Published online first: 6 March 2015

The past year has once again been a busy one for the biosimilars industry. One of the most important milestones during 2014 was the news that the US Food and Drug Administration (FDA) had accepted several biosimilars applications, and even recommended the approval of one product, moving the country one step closer to getting biosimilars on to the US market.

Sandoz, the generics division of Novartis, announced on 24 July 2014 that FDA had accepted its application for the company’s filgrastim biosimilar. Sandoz was the first company to announce it had filed for approval of a biological under the biosimilars pathway created in the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) [1].

South Korean biotechnology company Celltrion submitted its application for approval of its infliximab biosimilar to FDA on 8 August 2014 [2]. While US-based injectables specialist Hospira submitted a biosimilar application for its epoetin alfa biosimilar Retacrit to FDA on 16 December 2014 [3]. The submission marks Hospira’s first biosimilar application in the US and is the first US submission for an epoetin alfa biosimilar. Canada-based Apotex announced on 17 December 2014 that FDA had accepted the company’s application for a biosimilar version of Amgen’s Neulasta (pegfilgrastim) [4].

In a landmark decision, on 7 January 2015, advisers from FDA’s Oncologic Drugs Advisory Committee voted 14–0 in favour of the recommendation to approve Sandoz’s filgrastim biosimilar for all five indications of the originator product (Neupogen) [5].

FDA also granted tentative approval for a new insulin glargine product (LY2963016) on August 2014. The insulin glargine, called Basaglar in the US, is produced by US pharma company Eli Lilly and its partner Boehringer Ingelheim. The drug is intended to be a competitor to, and has the same amino acid sequence as, French drugmaker Sanofi’s diabetes drug Lantus (insulin glargine) [6]. The same product was approved in Europe as a biosimilar, Abasaglar (previously Abasria), in September 2014 [7].

In fact, the European Medicines Agency (EMA) has approved three biosimilars during 2014. As well as Abasaglar (insulin glargine), these included a filgrastim biosimilar (Accofil) from Accord Healthcare and a follitropin alfa biosimilar (Bemfola) from Finox Biotech [8]. The agency is also currently reviewing biosimilar applications for human insulin and etanercept [9].

Interestingly, a survey of diabetes sufferers concluded that if insulin biosimilars are significantly cheaper and equally effective, most patients will accept them [10]. Other companies working on insulin biosimilars include Mylan, Biocon, Sanofi [7], Merck and Samsung Bioepis (Samsung’s specialized biologicals unit) [11].

US generics company Alvogen launched its infliximab biosimilar Inflectra in Central and Eastern Europe in February 2014 in collaboration with Hospira [12].

Two biosimilars were also approved in Japan during 2014. Japanese pharma firm Nippon Kayaku launched its infliximab biosimilar, Infliximab BS, in Japan in November 2014 [13]. Sandoz received marketing authorization approval for its biosimilar filgrastim (Filgrastim BS Sandoz) in March 2014 [14].

A trastuzumab biosimilar, Herzuma, from South Korean biotechnology company Celltrion, was approved in South Korea in January 2014 [15].

The Russian Ministry of Health approved Russian biotechnology company Biocad’s non-originator biological rituximab, AcellBia (BCD-20), in April 2014 [16].

In a decision somewhat at odds with the rest of Europe, France introduced legislation allowing substitution of biosimilars, which came into effect on 1 January 2014 [17]. To date, no other EU country has explicitly authorized the substitution of biologicals from different manufacturers and a number of EU Member States have gone as far as banning this practice [18].

The contentious issue of how to name biosimilars was once again a hot topic for discussion during 2014. In July 2014, 32 organizations signed a letter calling on FDA to require biologicals and biosimilars to have the same International Nonproprietary Name (INN) [19]. However, to the contrary, in August 2014, more than 10 medical associations and 20 individual specialists sent a signed letter to FDA Commissioner Margaret Hamburg saying that biosimilars ‘must have distinguishable non-proprietary names’ [20]. In addition, the European Crohn’s and Colitis Organisation (ECCO) and the European Association for Bioindustries (EuropaBio) both called for distinguishable names for biosimilars in their respective position papers on biosimilars [21, 22].

The World Health Organization (WHO) drafted a proposal in 2014 for a biological qualifier (BQ), which would assign a four-letter alphabetic code to all biologicals [23]. However, Sandoz claimed that ‘no additional component is needed in most jurisdictions including the European Union, where existing naming systems, which require biologicals to be identified through the recording of brand name and batch number, have worked very well’. Also, according to the European Generic medicines Association (EGA), who represent the generics industry, ‘biosimilars have been used safely since 2006, and pharmacovigilance data shows that current tracking and adverse event reporting systems work well’ [24].

A survey conducted by the patient advocacy group RetireSafe was reported to have found that elderly patients in the US lack knowledge on biosimilars, but that they overwhelmingly support strong patient safeguards and notification of patients and physicians when biosimilar substitution takes place [25]. In addition, results of a survey carried out by ECCO highlighted a ‘lack of confidence in biosimilars and the need for continued education’ [26]. Results of a survey carried out by the Alliance for Safe Biologic Medicines (ASBM) was also reported to have highlighted a lack of knowledge, this time of physicians [27]. In response to this need for education, EGA has called upon national authorities and medical societies to actively engage in reducing the knowledge gap about biosimilars [28].

During 2014 additional state legislation has been considered that would allow the substitution of biosimilars, but with, in many cases, restrictions requiring physician and/or patient notification, as well as record keeping. The latest states to consider or pass legislation include Delaware, Idaho, Indiana, Massachusetts, and Pennsylvania [2932]. In a turnaround from its previous stance, the Generic Pharmaceutical Association (GPhA) announced on 9 December 2014 that it was supporting compromise legislation that would allow biosimilars designated as ‘interchangeable’ by FDA to be automatically substituted at the pharmacy [33]. The GPhA had previously stated that laws concerning biosimilar substitution were ‘premature and unnecessary at this time’ [34].

Guidelines have been a hot topic during 2014. EMA updated its overarching guidelines in 2014. The agency issued its revised guidelines on biosimilars quality in June 2014, on similar biological medicinal products in November 2014 and on non-clinical and clinical issues for biosimilars in December 2014. The guidelines come into effect on 1 December 2014, 30 April 2015 and 1 July 2015, respectively [3537]. The agency also issued a concept paper in March 2014 for revision of the immunogenicity guideline for biologicals. The guideline was open to comment from stakeholders until the end of June 2014 [38].

China’s Center for Drug Evaluation (CDE), which is part of CFDA (simplified Chinese: ), issued draft guidance on 29 October 2014 outlining the principles for developing biosimilars of biologicals already approved in China. The draft guidance was released for a one-month consultation period, which ended on 29 November 2014 [39].

Despite FDA issuing three draft guidance documents on biosimilars in February 2012 [40], the agency is still yet to issue final guidance. The agency did, however, release draft guidance on reference product exclusivity for biologicals [41] and guidance on how to use clinical pharmacology data to show biosimilarity to a reference product [42]. The agency also published its first-ever edition of the ‘Purple Book’ in September 2014, a new set of lists of licensed biological products and interchangeable biosimilars [43]. The sooner biosimilars hit the US market the sooner savings from these products can begin to be realized. According to an analysis carried out by the RAND Corporation, introducing biosimilars of complex biologicals used to treat illnesses, such as cancer and rheumatoid arthritis, could cut spending on biologicals in the US by US$44 billion over the next decade [44].

Sandoz has once again been leading the way in biosimilars’ development, with its landmark filgrastim biosimilar decision in the US [5]. The company claimed in December 2014 that results from a pivotal phase III clinical study of its filgrastim biosimilar (EP2006) had ‘demonstrated similarity’ with respect to safety and efficacy compared to Amgen’s Neupogen (filgrastim) [45]. These results were used in its US filing. The company also completed patient enrolment in its phase III trial with biosimilar etanercept (EGALITY). The trial aims to demonstrate the equivalent efficacy of Sandoz’s biosimilar etanercept (GP2015) and Amgen’s Enbrel in patients with moderate to severe chronic plaque-type psoriasis [46].

Meanwhile, Amgen has expanded its biosimilars portfolio to include nine different molecules. Biosimilars in its sights include Avastin (bevacizumab), Herceptin (trastuzumab) and Rituxan/MabThera (rituximab) from Roche, Erbitux (cetuximab) from Eli Lilly, Humira (adalimumab) from AbbVie, and Remicade (infliximab) from Johnson & Johnson [47]. The company started a global phase III trial of its biosimilar rituximab in 2014 and is also currently conducting two phase III clinical trials for its biosimilar adalimumab [48]. In November 2014 Amgen launched an app which aims to provide a source of information about biosimilars [49].

Preclinical assessments claimed that Amgen’s biosimilar bevacizumab candidate (ABP 215) is ‘highly similar’ to Avastin [50] and a primary efficacy analysis from a phase III trial of Amgen’s adalimumab biosimilar (ABP 501) compared with Humira (adalimumab) claimed that the products ‘demonstrated clinical equivalence’ [51]. Amgen is carrying out a global phase III clinical trial for a biosimilar version of Roche’s blockbuster arthritis/non-Hodgkin’s lymphoma drug MabThera/Rituxan (rituximab) [52]. The company has also started recruiting patients for a clinical trial to study the effect of switching patients from the originator biological Aranesp (darbepoetin alfa) to biosimilar epoetin alfa, in other words, from a long-acting to a short-acting epoetin [53].

However, despite Amgen’s recently increasing interest in biosimilars, it is still suing Sandoz to stop the biosimilars maker from marketing a biosimilar of its top-selling product Neupogen (filgrastim) in the US [54].

Polish biologicals company Mabion announced in November 2014 that it had received the consent of the appropriate regulatory authorities in Bosnia and Herzegovina, Croatia, Poland and Serbia to start a phase III clinical trial for its rituximab biosimilar (MabionCD20) in patients with diffuse large B-cell lymphoma [55]. US-based Momenta Pharmaceuticals also announced in December 2014 the acceptance by the UK Medicines and Healthcare Products Regulatory Agency of a clinical trial application to initiate a clinical trial for its adalimumab biosimilar, M923 [56].

The Polish Society of Gastroenterology started an observational trial to study the long-term safety of anti-tumour necrosis factor (TNF) antibodies, including biosimilars, in the treatment of inflammatory bowel disease (IBD) [57].

Analysis of results from a phase I trial of CKD Pharma’s darbepoetin alfa biosimilar (CKD-11101) compared with Nesp (darbepoetin alfa), were reported by CKD Pharma to show ‘a comparable pharmacokinetic, pharmacodynamic and tolerability profile to that of Nesp’ [58].

Phase I trials of pharma giant Pfizer’s biosimilar infliximab and rituximab candidates were reported to have found ‘similar pharmacokinetic properties compared to the originator products’ [59]. Pfizer also started recruiting patients in 2014 for its phase III biosimilar trastuzumab trial [60].

A retrospective analysis of cancer patients who received either originator rituximab (MabThera) or ‘similar biologic’ rituximab (Reditux) chemotherapy concluded that the two drugs had ‘comparable efficacy and safety’ [61].

Results from phase I and phase III clinical trials completed during 2014 reported the ‘bioequivalence’ and ‘clinical comparability’ of an infliximab biosimilar (BOW015) when compared to the originator product Remicade (infliximab) [6264] in non-inferiority trials, as well as the ‘safety of switching to biosimilar infliximab’ [65].

A phase III trial comparing Hanwha Chemical Corporation’s biosimilar etanercept, HD203, with Enbrel (etanercept) also reported equivalent efficacy [66].

A study of the treatment of patients with chronic kidney disease undergoing haemodialysis with ‘biocomparable’ and originator erythropoietin in Mexico reported ‘comparable’ efficacy (in terms of changes in haemoglobin levels) and safety [67]. Additionally, a post-authorization observational safety study of Hospira’s biosimilar epoetin product Retacrit/Silapo (epoetin zeta) reported that the safety profile in patients with renal anaemia was ’comparable to data reported for other epoetin alfa products’ [68].

Studies of the biosimilar granulocyte colony-stimulating factor (G-CSF), Nivestim, with the originator G-CSF, Neupogen (filgrastim), reported that ‘there were no statistical differences when used for the mobilization of peripheral blood stem cells in patients treated for haematological malignancies’ [69, 70].

An adalimumab biosimilar (CHS-1420) from fledgling biotech company Coherus Biosciences was reported to have met the criteria for comparable pharmacokinetics in a clinical study in healthy subjects [71]. The company also started a phase III trial in June 2014 for its etanercept biosimilar [72].

A study of the use of epoetin biosimilars in the therapeutic management of anaemia secondary to chemotherapy in haematology and oncology concluded that the biosimilars ‘were effective and well tolerated in the management of chemotherapy-induced anaemia in patients with solid tumours, lymphoma and myeloma’ [73].

Extrapolation of indications was also a topic of interest during 2014. 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 [74]. However, results of a survey carried out by ECCO found that most respondents (63.7%) claimed they would not switch a patient onto a biosimilar monoclonal antibody, until there was sufficient disease-specific evidence about their interchangeability [75].

However, EMA justified its decision on extrapolation of indications in approval of biosimilar epoetins and filgrastim, stating that ‘to date, no specific efficacy or safety issues have been identified in clinical practice for biosimilar epoetins licensed in Europe’ and that ‘post-marketing studies have confirmed the efficacy and safety of filgrastim biosimilars in the approved indications’ [76, 77]. Despite this assurance by the European regulator, many medical societies, including the American College of Rheumatology, the European CanCer Organisation, the Mexican College of Rheumatology, the Portuguese Society of Rheumatology, and the Spanish Society of Gastroenterology [7880] have all specifically recommended against the use of biosimilars in extrapolated indications.

Biosimilar deals were also popular during 2014. Some notable deals made during 2014 include those of Epirus Switzerland, a subsidiary of US-based Epirus Biopharmaceuticals (Epirus) and India-based Ranbaxy Laboratories for BOW015, an infliximab ‘similar biologic’ [81]. Meanwhile, Epirus and Livzon agreed to collaborate on copy biologicals for China [82]. Swedish biotech company Xbrane Bioscience signed an agreement with a global Indian pharmaceutical company to assist them in developing an optimized production system for a specific biosimilar that will be marketed worldwide [83]. South Korea-based LG Life Sciences and Japan-based Mochida Pharmaceutical made a deal in October 2014 to co-develop and commercialize an adalimumab biosimilar for the Japanese market [84].

Other deals made during 2014 include those of PlantForm Corporation and PharmaPraxis, Oncobiologics and Laboratorios Liomont [85], Cipla and Mabpharm, Strides Arcolab and Oncobiologics, NeuClone and the Serum Institute [86], Oncobiologics and IPCA Labs [87], Kissei and Alteogen [88], Catalent and Zhejiang Hisun Pharma [89], and Lupin Pharmaceuticals and Yoshindo [90].

Meanwhile, India’s drug regulator, the Drugs Controller General of India (DCGI), granted marketing approval for the infliximab ‘similar biologic’ BOW015 in September 2014 [91]. India-based Biocon introduced its trastuzumab ‘similar biologic’ CANMAb to the Indian market in January 2014 [92]. This was followed by Mylan’s Indian subsidiary launching its trastuzumab ‘similar biologic’ Hertraz in February 2014 [93]. India-based active pharmaceutical ingredient (API) supplier Hetero launched its darbepoetin alfa ‘similar biologic’ in India in June 2014 [94].

Previously, in February 2014, India-based biologicals specialist Biocon and US generics maker Mylan challenged India’s Delhi High Court interim order barring them from using Roche’s data to sell their ‘similar biologic’ versions of Roche’s breast cancer blockbuster Herceptin (trastuzumab) [95].

Finally, biopharmaceutical giant Amgen and US generics maker Actavis spoke to GaBI about their views on biosimilars and their biosimilar plans [96].

The increasing number of clinical trials being carried out for biosimilars, the number of global biosimilar approvals, the first FDA recommendation, and the growing number of biosimilar applications in the US, all suggest the future looks bright for the biosimilars’ market in 2015.

According to a report published by IMS Health in October 2014, the use of biosimilars in Europe; however, still varies widely between countries and therapeutic areas [97]. This report highlighted the need for continuing education of patients, prescribers and healthcare payers.

Competing interests: None.

Provenance and peer review: Article prepared based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

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51.GaBI Online – Generics and Biosimilars Initiative. Phase III study of biosimilar adalimumab meets primary endpoint [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Phase-III-study-of-biosimilar-adalimumab-meets-primary-endpoint
52.GaBI Online – Generics and Biosimilars Initiative. Amgen starts phase III trial for biosimilar rituximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Amgen-starts-phase-III-trial-for-biosimilar-rituximab
53.GaBI Online – Generics and Biosimilars Initiative. Study into switching from Aranesp to biosimilar epoetin alfa [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Study-into-switching-from-Aranesp-to-biosimilar-epoetin-alfa
54.GaBI Online – Generics and Biosimilars Initiative. Amgen sues Sandoz over filgrastim biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Amgen-sues-Sandoz-over-filgrastim-biosimilar
55.GaBI Online – Generics and Biosimilars Initiative. Mabion starts phase III trial for rituximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Mabion-starts-phase-III-trial-for-rituximab-biosimilar
56.GaBI Online – Generics and Biosimilars Initiative. Momenta gains approval to start biosimilar adalimumab trial in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Momenta-gains-approval-to-start-biosimilar-adalimumab-trial-in-Europe
57.GaBI Online – Generics and Biosimilars Initiative. Long-term safety study of biosimilar anti-TNF initiated [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Long-term-safety-study-of-biosimilar-anti-TNF-initiated
58.GaBI Online – Generics and Biosimilars Initiative. Phase I study shows darbepoetin alfa biosimilar to be well tolerated [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Phase-I-study-shows-darbepoetin-alfa-biosimilar-to-be-well-tolerated
59.GaBI Online – Generics and Biosimilars Initiative. Phase I studies of infliximab and rituximab biosimilars demonstrate pharmacokinetic similarity [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Phase-I-studies-of-infliximab-and-rituximab-biosimilars-demonstrate-pharmacokinetic-similarity
60.GaBI Online – Generics and Biosimilars Initiative. Pfizer to start phase III biosimilar trastuzumab trial [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Pfizer-to-start-phase-III-biosimilar-trastuzumab-trial
61.GaBI Online – Generics and Biosimilars Initiative. Rituximab ‘similar biologic’ shows equivalent efficacy and safety [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Rituximab-similar-biologic-shows-equivalent-efficacy-and-safety
62.GaBI Online – Generics and Biosimilars Initiative. Positive phase I data for infliximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Positive-phase-I-data-for-infliximab-biosimilar
63.GaBI Online – Generics and Biosimilars Initiative. Positive phase III data for Epirus infliximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Positive-phase-III-data-for-Epirus-infliximab-biosimilar
64.GaBI Online – Generics and Biosimilars Initiative. Biosimilar infliximab comparable to Remicade [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilar-infliximab-comparable-to-Remicade
65.GaBI Online – Generics and Biosimilars Initiative. Study results show safety of switching to biosimilar infliximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Study-results-show-safety-of-switching-to-biosimilar-infliximab
66.GaBI Online – Generics and Biosimilars Initiative. Biosimilar etanercept demonstrates equivalent efficacy [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilar-etanercept-demonstrates-equivalent-efficacy
67.GaBI Online – Generics and Biosimilars Initiative. Biocomparable has comparable safety and efficacy to originator erythropoietin in haemodialysis patients [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biocomparable-has-comparable-safety-and-efficacy-to-originator-erythropoietin-in-haemodialysis-patients
68.GaBI Online – Generics and Biosimilars Initiative. Biosimilar epoetin shows good safety profile in post-authorization study [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilar-epoetin-shows-good-safety-profile-in-post-authorization-study
69.GaBI Online – Generics and Biosimilars Initiative. Biosimilar G-CSF safe for mobilization of stem cells [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilar-G-CSF-safe-for-mobilization-of-stem-cells
70.GaBI Online – Generics and Biosimilars Initiative. Mobilization of stem cells by biosimilar Nivestim and Neupogen [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Mobilization-of-stem-cells-by-biosimilar-Nivestim-and-Neupogen
71.GaBI Online – Generics and Biosimilars Initiative. Adalimumab biosimilar has comparable pharmacokinetics to Humira [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Adalimumab-biosimilar-has-comparable-pharmacokinetics-to-Humira
72.GaBI Online – Generics and Biosimilars Initiative. Coherus starts phase III biosimilar etanercept trial [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Coherus-starts-phase-III-biosimilar-etanercept-trial
73.GaBI Online – Generics and Biosimilars Initiative. Biosimilars in the treatment of chemotherapy-induced anaemia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilars-in-the-treatment-of-chemotherapy-induced-anaemia
74.GaBI Online – Generics and Biosimilars Initiative. Efficacy, extrapolation and interchangeability of biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Efficacy-extrapolation-and-interchangeability-of-biosimilars
75.GaBI Online – Generics and Biosimilars Initiative. Extrapolation of indications in biosimilars: infliximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Extrapolation-of-indications-in-biosimilars-infliximab
76.GaBI Online – Generics and Biosimilars Initiative. Extrapolation of indications in biosimilars: epoetin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Extrapolation-of-indications-in-biosimilars-epoetin
77.GaBI Online – Generics and Biosimilars Initiative. Extrapolation of indications in biosimilars: filgrastim [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Extrapolation-of-indications-in-biosimilars-filgrastim
78.GaBI Online – Generics and Biosimilars Initiative. Extrapolation of biosimilar infliximab indications to inflammatory bowel disease [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Extrapolation-of-biosimilar-infliximab-indications-to-inflammatory-bowel-disease
79.GaBI Online – Generics and Biosimilars Initiative. ABPI issues updated position paper on biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/General/ABPI-issues-updated-position-paper-on-biosimilars
80.GaBI Online – Generics and Biosimilars Initiative. Use of biosimilars in rheumatology [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/Research/Use-of-biosimilars-in-rheumatology
81.GaBI Online – Generics and Biosimilars Initiative. Epirus and Ranbaxy sign agreement for infliximab ‘similar biologic’ [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Epirus-and-Ranbaxy-sign-agreement-for-infliximab-similar-biologic
82.GaBI Online – Generics and Biosimilars Initiative. Epirus and Livzon collaborate on copy biologicals for China [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Epirus-and-Livzon-collaborate-on-copy-biologicals-for-China
83.GaBI Online – Generics and Biosimilars Initiative. Xbrane signs biosimilar optimization deal with Indian pharma firm [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Pharma-News/Xbrane-signs-biosimilar-optimization-deal-with-Indian-pharma-firm
84.GaBI Online – Generics and Biosimilars Initiative. LG Life Sciences and Mochida make deal for adalimumab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/LG-Life-Sciences-and-Mochida-make-deal-for-adalimumab-biosimilar
85.GaBI Online – Generics and Biosimilars Initiative. More biosimilars collaborations on the cards [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/More-biosimilars-collaborations-on-the-cards
86.GaBI Online – Generics and Biosimilars Initiative. Biosimilars deals coming thick and fast [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Biosimilars-deals-coming-thick-and-fast
87.GaBI Online – Generics and Biosimilars Initiative. Oncobiologics and IPCA create biosimilars alliance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Oncobiologics-and-IPCA-create-biosimilars-alliance
88.GaBI Online – Generics and Biosimilars Initiative. Kissei makes biosimilars deal with Alteogen [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Kissei-makes-biosimilars-deal-with-Alteogen
89.GaBI Online – Generics and Biosimilars Initiative. Biosimilar merger for Epirus and collaboration for Catalent [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Biosimilar-merger-for-Epirus-and-collaboration-for-Catalent
90.GaBI Online – Generics and Biosimilars Initiative. Lupin and Yoshindo start biosimilars joint venture [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Lupin-and-Yoshindo-start-biosimilars-joint-venture
91.GaBI Online – Generics and Biosimilars Initiative. Infliximab ‘similar biologic’ receives Indian approval [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Infliximab-similar-biologic-receives-Indian-approval
92.GaBI Online – Generics and Biosimilars Initiative. Trastuzumab ‘similar biologic’ to be launched in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Trastuzumab-similar-biologic-to-be-launched-in-India
93.GaBI Online – Generics and Biosimilars Initiative. Mylan launches trastuzumab ‘similar biologic’ in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Mylan-launches-trastuzumab-similar-biologic-in-India
94.GaBI Online – Generics and Biosimilars Initiative. Darbopoetin alfa ‘similar biologic’ launched in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Darbopoetin-alfa-similar-biologic-launched-in-India
95.GaBI Online – Generics and Biosimilars Initiative. Biocon and Mylan challenge Indian ban on trastuzumab ‘similar biologics’ [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Biosimilars/News/Biocon-and-Mylan-challenge-Indian-ban-on-trastuzumab-similar-biologics
96.Biosimilars collaboration at Amgen and Actavis. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):155-6. doi:10.5639/gabij.2014.0303.035
97.GaBI Online – Generics and Biosimilars Initiative. Biosimilars use in Europe varies widely [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 24]. Available from: www.gabionline.net/Reports/Biosimilars-use-in-Europe-varies-widely

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2015 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


Last update: 12/02/2019

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Reducing the European healthcare budget with generics and biosimilars

The world market for medicinal products is expected to reach US$1 trillion in 2014. Global spending on medicines is expected to grow to nearly US$1.2 trillion by 2017 [1]. As governments around the world try to rein in healthcare expenses, generics and biosimilars can play a major role in reducing this budgetary burden.

Intellectual property

Intellectual property (IP) rights are of critical value in a knowledge-based society and pharmaceutical companies are particularly dependent on appropriate patent protection and enforcement. Equally, effective competition between originator and generic drugs generates incentives for originator pharmaceutical companies to continue investing in research and development.

Budget constraints

Due to a combined effect of the so-called ‘patent cliff’ (when a large number of key small molecule brand-name drugs become open to competition from generics) and the current economic crisis, in recent years most OECD (Organisation for Economic Co-operation and Development) countries have even experienced a consolidation or decrease in pharmaceutical expenditure as a share of total healthcare expenditure. Most of these savings have been achieved by the replacement of expensive brand-name drugs with low cost generics.

Other changes have also been introduced to reduce spending on medicines. Changes affecting reimbursement lists and procedures, e.g. de-listings, introduction of positive and/or negative lists; and the reference price system, i.e. changes in pricing methodology allowing lower reference prices, broader clusters of similar medicines, and/or the pricing of generics in a cluster (‘generic price link’) are being made.

Measures to increase the uptake of generics, such as making prescribing by international non-proprietary name mandatory and the use of public awareness-raising campaigns, have been frequently used.

Despite these measures, pharmaceutical expenditure still accounts for a considerable percentage of total healthcare spending in Europe. In 2011, spending on drugs as a percentage of total healthcare spending ranged from 6.8% in Denmark to 33.4% in Hungary; followed by Greece (28.5%) and the Slovak Republic (27.4%).

European Union measures

The European Union (EU) has introduced several measures, such as a centralized procedure for the authorization of medicines, rules facilitating the approval of generics, support to small- and medium-sized enterprises (SMEs), and regulatory data protection incentives to promote innovation while assuring timely access of patients to medicines.

Biosimilars

Biosimilars can also play a major role in improving public health since they address the need for the responsible allocation of public funds while opening up promising treatment options for patients by increasing their affordability. However, to realize the potential benefits that biosimilars offer requires not only a robust regulatory framework such as the one in place in the EU, but also effective risk management.

Experience to date suggests that the most important conditions required for market uptake of biosimilars are factors such as:

  1. physician perception
  2. patient acceptance
  3. local pricing and reimbursement regulations
  4. procurement policies and terms.

Fostering the informed uptake and improving early access to high quality biosimilars on the basis of the EU’s regulatory framework, i.e. through access to unbiased information and education of patients, healthcare professionals and payers, while closely monitoring the EU’s market penetration of biosimilars may contribute to the success of the dual objectives of improving overall public health and the sustainability of Member States’ healthcare systems.

According to IMS Health, although biosimilars are a small segment in the total pharmaceutical market (~1%), they have experienced exceptional growth (38% in 2012). Biosimilars’ share of the accessible European market has grown steadily from their launch and is now at 18%. Biosimilars have a 13% share of the growth hormone market, 19% of the erythropoietin market, and 49% of the granulocyte colony-stimulating factor market [2].

The per capita uptake of biosimilars and the size of the accessible market however differ between European markets [3]. For example, in the UK biosimilars make up only 30% of the volume market share of their reference products, despite the fact that the UK has one of the highest market shares of generics in Europe. In 2010, 83% of prescriptions in England were prescribed and 67% were dispensed as generics [4]. The UK biosimilars uptake is significantly lower than in Germany, where biosimilars have around 50% volume uptake [5].

Continued effort

Member States’ governments will need to continue their efforts to limit the future growth in medical expenditures, especially for medicines. The use of generics and biosimilars is therefore expected to be promoted as a lower-cost alternative by public and private payers. However, lack of competition and insufficient or ineffective policies promoting the use of generics and biosimilars can limit the ability of governments to implement budgetary savings.

Competing interests: None.

Provenance and governance: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board, internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. European Commission. Commission staff working document. Pharmaceutical industry: a strategic sector for the European economy. 1 August 2014. SWD(2014) 216 final/2 [homepage on the Internet]. 2014 Aug 1 [cited 2014 Oct 16]. Available from: http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/pharmastrategy_en.pdf
2. Dunn C. Biosimilar accessible market: size and biosimilar penetration. Prepared for EFPIA-EGA
-EuropaBio, April 2012.
3. GaBI Online – Generics and Biosimilars Initiative. Use of biosimilars in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Oct 16]. Available from: www.gabionline.net/Reports/Use-of-biosimilars-in-Europe
4. Health and Social Care Information Centre. Prescriptions Dispensed in the Community Statistics for England – 2000-2010 [NS]. 27 July 2011 [homepage on the Internet]. 2014 Oct 16 [cited 2014 Oct 16]. Available from: http://www.hscic.gov.uk/pubs/presdisp2000–10
5. GaBI Online – Generics and Biosimilars Initiative. UK biosimilars uptake lower than in some other EU countries [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Oct 16]. Available from: www.gabionline.net/Reports/UK-biosimilars-uptake-lower-than-in-some-other-EU-countries

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2015 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


Last update: 18/02/2019

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ECCO 2013 survey highlights lack of confidence in biosimilars

Results of a survey carried out by the European Crohn’s and Colitis Organisation (ECCO) highlight a lack of confidence in biosimilars and the need for continued education.

The results of the ECCO 2013 survey [1] were presented by Dr Alessandro Armuzzi, together with the EU physician 2013 survey on naming, transparency and traceability for biosimilars conducted by the Alliance for Safe Biologic Medicines [2] at the EuropaBio (European Association for Bioindustries) roundtable held on 18 March 2014 in Brussels, Belgium.

The survey was carried out in order to study whether inflammatory bowel disease (IBD) specialists were aware of biosimilars. The survey consisted of a 15-question anonymous web survey, for which ECCO members were randomly invited by email to participate.

Of the 307 ECCO members that completed the survey, most (69.5%) realized that monoclonal antibody biosimilars were ‘similar’ but not identical to their respective originator biological. The majority of respondents (89.4%) also thought that such biosimilars would be cheaper than the originator products. On the other hand, 62.4% of respondents thought that monoclonal antibody biosimilars were more complex compared to other biosimilars and therefore more at risk of ‘not being similar enough’.

Substitution

On the subject of pharmacist substitution of originator biologicals by biosimilars, 85% of respondents were not in favour of automatic substitution, although 18% would support such substitution for new prescriptions.

Interchangeability

When considering interchangeability of originator biologicals and biosimilars, most of the respondents (63.7%) said that they would not switch a patient onto a biosimilar monoclonal antibody as there is no disease-specific evidence about their interchangeability.

Confidence

When questioned as to whether they were confident about prescribing biosimilars, less than half (39%) of respondents felt confident. The majority (61%) of respondents were either not confident (32.7%) or only a little confident (28.3%) about prescribing biosimilars.

Dr Armuzzi concluded that IBD specialists are generally informed about biosimilars and see them as an opportunity to reduce costs. However, they do not see biosimilars as interchangeable and are not confident about the use of biosimilars in clinical practice.

Acknowledgment

The editors wish to thank Dr Alessandro Armuzzi, Inflammatory Bowel Disease Unit, Complesso Integrato Columbus, Catholic University, Rome, Italy, for his helpful comments and inputs.

Competing interests: None.

Provenance and peer review: Not commissioned; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. Armuzzi A. A clinician’s perspective on recent prescribers’ surveys. EuropaBio and the Alliance for Safe Biologic Medicines (ASBM) Roundtable on Naming, transparency and traceability for biosimilars: does Europe need to act? 18 March 2014; Brussels, Belgium.
2. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 20143;3(2):58-5. doi: 10.5639/gabij.2014.0302.018

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2014 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

 


Last update: 30/01/2019

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New EU guidance for the evaluation of medicinal products with modified drug release will be finished by the middle of 2014

Submitted: 2 March 2014; Revised: 7 March 2014; Accepted: 8 March 2014; Published online first: 21 March 2014

The guideline ‘Note for guidance on modified release oral and transdermal dosage forms: Section II (Pharmacokinetic and clinical evaluation)’ [1] was issued over 10 years ago, and the need for revision was recognized in 2010. An international group of experts, led by Austrian members of the Pharmacokinetics Working Party, is responsible for its implementation. They have joined forces with the Quality Working Party, which revises guidelines on the quality of such products, and various other expert groups of the European Medicines Agency (EMA). A draft version was recently produced and approval obtained from EMA’s Committee for Medicinal Products for Human Use; it was then posted on the EMA website for feedback [2].

This guideline deals specifically with medicinal products that use a modified drug release mechanism. Several different product groups, in particular all modified oral dosage forms, all transdermal delivery systems, as well as subcutaneous or intramuscular depot formulations, are covered by the recommendations.

Two principles of the modification can be distinguished:

  1. Delayed drug release products: those with enteric coating, for example, that either protects the drug from the acidic pH in the stomach or protects the stomach from a potentially harmful drug. Other products target a specific location in the lower digestive tract for time-dependent, belated drug release, thereby significantly increasing the efficiency of certain drugs.
  2. Prolonged release products: those products that release quantities of the active ingredient continuously over a certain time period. Peaks in drug concentrations in the blood can be flattened by this mechanism, and more uniform drug concentrations are achieved in contrast to immediate release formulations. Therefore, the incidence and intensity of undesired, concentration-dependent side effects can be reduced and dosing frequency decreased. The reduction in dosing frequency can also lead to improved patient compliance or adherence.

Today, numerous different release mechanisms are increasingly being incorporated into new products. The simultaneous use of galenic components with both immediate and prolonged release properties achieves a rapid onset of action combined with a prolonged duration of effects. In people suffering from chronic diseases where treatment needs to be adjusted to a circadian rhythm of their symptoms, a time-related single or multiple drug release, a so-called pulsatile release, from a single tablet might lead to improved treatment outcome.

The new guideline will provide detailed rules for the conduct of clinical trials of these drug products. These guidelines will include:

  • Approval of a new drug with a modified release mechanism.
  • Approval of an already known active ingredient, with a new modified release mechanism.
  • Approval of a generic version of an already approved product that uses a modified release mechanism.

Two new, additional pharmacokinetic parameters to be used for the evaluation and comparison of the plasma profile of drugs were established during the guideline revision process: Cτ (concentration at the end of the dosing interval) and partialAUC (the area under the concentration time curve during a predefined and relevant portion of the whole AUC).

The necessity and usefulness of conducting bioequivalence studies after repeated dosing (steady-state or multiple dose studies) was discussed in detail, and the latest scientific publications related to this topic were also taken into account. In contrast to applicable US FDA guidelines, it was decided to continue to request these studies as a requirement for the approval of certain generic drugs [3]. The failure to conduct such a study, however, can be justified by proving that no or negligible accumulation of the active substance will occur in patients following the recommended dosage regimen.

The intensity of the discussions is reflected in the fact that 22 draft versions were developed before publication of internal draft 23 on 15 March 2013. The deadline for receipt of comments closed on 15 September 2013. Over 400 pages containing thousands of comments have been received from industry representatives, doctors and patient organizations, and these are now being carefully evaluated, discussed and responded to. By the middle of 2014, a new version of the guideline, incorporating these discussions and comments, will be made available.

Competing interests: None.

Provenance and peer review: Not commissioned; internally peer reviewed.

Co-author

Jan Neuhauser, MD
AGES MEA/BASG

References
1. European Agency for the Evaluation of Medicinal Products. Note for guidance on modified release oral and transdermal dosage forms: Section II (Pharmacokinetic and clinical evaluation). CPMP/EWP/280/96 Corr *. 28 July 1999 [homepage on the Internet]. 2009 May 27 [cited 2014 Mar 7]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003126.pdf
2. European Medicines Agency. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms. EMA/CPMP/EWP/280/96 Corr1. Draft XXIII. 21 February 2013 [homepage on the Internet]. 2013 Aug 19 [cited 2014 Mar 7]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140482.pdf
3. Baumgärtel C. New product-specific bioequivalence guidance. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):29. doi: 10.5639/gabij.2014.0301.009

Author for correspondence: Christoph Baumgärtel, MD, MSc, Department Head, Department Safety and Efficacy Assessment of Medicinal Products, Institute Marketing Authorisation of Medicinal Products & LCM, AGES MEA–Austrian Medicines and Medical Devices Agency, and Austrian Federal Office for Safety in Health Care (BASG), European Expert in Pharmacokinetics Working Party of EMA, Member of Austrian Prescription Commission, 5 Traisengassee, AT-1200 Vienna, Austria

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2014 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


Last update: 18/02/2019

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International Alliance of Patients’ Organizations toolkit for biological and biosimilar medicines

The International Alliance of Patients’ Organizations (IAPO) is an alliance of over 200 patient groups that represents the interests of patients worldwide. In November 2013, IAPO published its Information and Advocacy Toolkit on Biological and Biosimilar Medicines for Patients’ Organizations [1]. The Toolkit was developed to provide up-to-date, evidence-based information on the science, technology, and regulatory information relevant to biological and biosimilar medicines.

IAPO believes patients should be aware of what biological and biosimilar medicines are and the implications of their increasing availability. The Toolkit was developed to allow patient advocates to make informed judgements on the value of biological and biosimilar medicines and actively engage in debate and discussion with other stakeholders involved in health care.

The Toolkit contains a briefing paper on biological and biosimilar medicines, a quick guide, a guide on what patients’ organizations can do, as well as a number of fact sheets. It is available free of charge to patients’ organizations around the world. It is unique in that it explores the perspectives of a variety of different stakeholders including patients’ organizations, regulators, medical associations, academics and biological and biosimilar medicine manufacturers.

IAPO’s Toolkit covers important issues for patients’ organizations and other stakeholders, identified through an online consultation and through in-depth interviews. Topics include the safety of biological medicines, how they are regulated and monitored, how they are prescribed and dispensed, as well as who can access them and what information and support is available to patients.

In December 2012, IAPO held an online consultation with its members to understand the level of awareness of biological and biosimilar medicines, their regulation and use, and the issues and concerns that patients’ organizations found most important. Raising patient awareness is essential, since the acceptance of generics substitution worldwide has been slow, with research showing that many patients get confused or feel apprehensive about having their drugs changed [2].

IAPO found varied awareness of biosimilar medicines among respondents. Most (54%) of the patients’ organizations that responded represented patients who were currently using biological medicines for treatment of their disease, and 20% of the respondents represented patients who were using biosimilar medicines. The majority of respondents had no (36%) or some (32%) awareness of how biosimilar medicines were regulated in their country or region.

Ensuring the safety of biosimilar medicines is an important issue for patients’ organizations. Safety includes a broad range of issues from how biosimilars are defined and named, to their ability to cause immune reactions, regulation and pharmacovigilance.

Pharmacovigilance is critical in ensuring the safety of all medicines. As all biological medicines can potentially cause an immune response after approval, surveillance and monitoring are absolutely essential to track any adverse effects caused by the medicine [3, 4].

IAPO’s online consultation revealed that 50% of respondents had some to high awareness of the pharmacovigilance system in their country while 33% had little awareness and 19% had no awareness at all. A number of patients’ organizations from both developed and developing countries highlighted the importance of a strong pharmacovigilance system, and how this was lacking in their countries.

Pharmacovigilance depends on being able to track and trace biological and biosimilar medicines. Being able to differentiate between medicines is essential [5]. Manufacturers of medicines can apply to the World Health Organization for an International Nonproprietary Name (INN). INNs facilitate the identification of pharmaceutical substances or active ingredients in medicines [6]. Each unique INN, sometimes called a generic name, is different to the brand name but shared between identical pharmaceutical substances. INNs are important for the clear identification, safe prescription and dispensing of medicines to patients, and for communication and exchange of information among healthcare professionals and scientists. However, the structural complexity of biological medicines means that a biosimilar cannot be identical to the original biological medicine or to other biosimilars.

If doctors or pharmacists use only the INN when prescribing a biological or biosimilar medicine, and if several biosimilars exist, it will not be known exactly which medicine the patient is being given. If an adverse effect occurs it will not be clear which medicine – either the original biological or any of several biosimilars – caused it [4]. Automatic substitution of approved biosimilars by the pharmacist without notifying the patient and physician/healthcare provider would circumvent pharmacovigilance, putting patient safety at risk [7], as could prescribing medicines using only the brand name.

Each biosimilar medicine should have a unique identifier (or brand name) in addition to its INN to make it clear which medicine a patient is taking [8, 9]. Patients should ensure that when they are prescribed a biological or biosimilar medicines they know the unique identifier (or brand name), manufacturer’s name and where to find the batch number of their medicine.

Biological medicines have revolutionized the treatment of many diseases and have benefited millions of patients worldwide. IAPO believes that ensuring access to high quality, safe and efficacious biological and biosimilar medicines depends on education of patients, doctors and health authorities. Stringent regulatory guidelines based on those of the European Medicines Agency, World Health Organization or US Food and Drug Administration, and robust pharmacovigilance and adverse event monitoring systems are key to ensuring patient safety.

To see the Toolkit and for more information on IAPO’s work on biological and biosimilar medicines please visit www.patientsorganizations.org/biosimilars

Competing interests: None.

Provenance and governance: Article abstracted based on the summary paper prepared by Ms Yasemin Dil, IAPO, UK; internally peer reviewed.

Bea Perks, PhD, GaBI Journal Editor

References
1. International Alliance of Patients’ Organizations (IAPO). Biological and biosimilar medicines: an information and advocacy toolkit for patients’ organizations, 2013 [homepage on the Internet]. [cited 2014 Sep 9]. Available from: http://www.patientsorganizations.org/showarticle.pl?id=1763&n=961
2.
Håkonsen H, Toverud E-L. A review of patient perspectives on generics substitution: what are the challenges for optimal drug use. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):28-32. doi:10.5639/gabij.2012.0101.008
3. EuropaBio. Guide to biosimilars: a focus on biosimilar medicines. 26 October 2011 [homepage on the Internet]. [cited 2014 Sep 9]. Available from: http://www.europabio.org/guide-biological-medicines-focus-biosimilar-medicines
4. Schellekens H. How similar do ‘biosimilars’ need to be? Nat Biotechnol. 2004;22(11): 1357-9.
5. Mellstedt H, Niederwieser D, Ludwig, H. The challenge of biosimilars. Ann Oncol. 2008;19(3):411-9.
6. World Health Organization. International Nonproprietary Names [homepage on the Internet]. [cited 2014 Sep 9]. Available from: www.who.int/medicines/services/inn/en/
7. Wyatt JS. Legislative efforts to limit prescription information sharing between patients and healthcare providers represent a serious threat to the health and safety of the American nation. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):165. doi:10.5639/gabij.2013.0204.045
8. Alexander EA. The biosimilar name debate: what’s at stake for public health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):10-2. doi:10.5639/gabij.2014.0301.005
9. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi.10.5639/gabij.2014.0302.018

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2015 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.


Last update: 14/02/2019

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Top developments in biosimilars during 2013

The past year has been a busy one for the biosimilars industry. Perhaps one of the most important milestones during 2013 was the European approval of the first monoclonal antibody biosimilar [Remsima/Inflectra (infliximab)] made as a collaboration by South Korean biotechnology company Celltrion and US-based generics major Hospira [1]. Celltrion has also gained approval for Remsima in South Korea [2] and Colombia [3], and has applied for approval in Japan [4].

In fact in Europe, the European Medicines Agency (EMA) has been busy during 2013 approving five biosimilars during the year. As well as Remsima and Inflectra, these included a filgrastim biosimilar (Grastofil) from Apotex, a follitropin alfa biosimilar (Ovaleap) from Teva Pharmaceutical Industries and a somatropin biosimilar (Somatropin Biopartners) from Switzerland-based biotech company Biopartners [5]. The agency is also currently reviewing biosimilar applications for follitropin alfa and insulin glargine [6].

Perhaps the hottest debated topic during 2013 has been the issue of how to name biosimilars at both the international and national level. Healthcare giant Johnson & Johnson is just the latest stakeholder to add its opinion to the ongoing debate by sending a Citizen Petition to the US Food and Drug Agency (FDA) asking the agency to require biosimilars to bear non-proprietary names that are similar to, but not the same as, those of their reference products or of other biosimilars [7]. Whereas in October 2013, a letter was sent to FDA by a bipartisan group of US senators calling for biosimilars to have the same active ingredient name as the brand-name originator product. Swiss drug giant Novartis also submitted a petition to FDA in October 2013 calling for biosimilars to ‘share the same International Nonproprietary Name (INN) as the reference product’. Originator biologicals developer Amgen, on the other hand, supports the use of distinguishable names [8]. During the October 2013 World Health Organization’s meeting on INNs for pharmaceuticals stakeholders, including the European Generic medicines Association (EGA), called for biosimilars to be assigned the same INN as their reference biologicals. While others, including the Alliance for Safe Biologic Medicines (ASBM), called for the use of distinct non-propriety names for biological medicines [9].

Another significant development in the US during 2013 was the passing or rejection of state legislation allowing the substitution of biosimilars, but with, in many cases, restrictions requiring physician and/or patient notification, as well as record-keeping [10,11].

EMA has also drafted new guidelines during the last year. The agency issued a draft concept paper on comparing quality in biologicals and biosimilars in June 2013. The guideline was open to comment from stakeholders until the end of September 2013 [12]. EMA also held a workshop in October 2013 as part of the agency’s public consultation exercise on its three draft revised overarching guidelines on biosimilars [13].

Canada’s regulatory agency, Health Canada, clarified in August 2013 that drugmakers seeking approval of similar drugs containing low molecular weight heparins (LMWHs) should use the approval pathway for subsequent entry biologicals [14]. There has been much debate over whether LMWHs should be considered as biosimilars or not.

One disappointing aspect of 2013 was the lack of progress made in the US. In February 2012, FDA issued three draft guidance documents on biosimilars to assist industry in developing such products [15]. However, despite almost a year having passed since then, the agency has yet to issue final guidance and there have still been no biosimilars approved using the biosimilars pathway in the US. FDA did manage to introduce its user fee programme during 2013 [16] and issued draft guidance for biosimilar meetings [17].

Sandoz, the generic drug division of Swiss drug giant Novartis, has once again been leading the way in biosimilars development. The company announced in December 2013 the start of a phase III clinical trial for a biosimilar version of the tumour necrosis factor inhibitor monoclonal antibody adalimumab in patients suffering from psoriasis [18]. Sandoz also demonstrated the innovative nature of biosimilars manufacturers with the launch in September 2013 of a new device for its somatropin biosimilar. The device aims to simplify the administration of the human growth hormone by using cartridges that require no reconstitution or priming, and a sliding injection button that requires minimum force to operate [19].

Sandoz reported the ‘similarity’, in a non-clinical study, with respect to in vitro and in vivo characteristics, of biosimilar etanercept (GP2015) and its reference product, Amgen’s blockbuster autoimmune disease treatment Enbrel (etanercept) [20]. Fledgling biotech company Coherus Biosciences reported ‘similar pharmacokinetics’ for its biosimilar etanercept (CHS-0214) in a pivotal clinical study [21]. Sandoz started a phase III clinical trial for biosimilar etanercept in patients suffering from psoriasis in May 2013 [22]. Samsung Bioepis initiated a phase III clinical trial for its biosimilar etanercept (SB4) during 2013, comparing SB4 to Enbrel, in terms of American College of Rheumatology 20% response criteria (ACR20) response rate in subjects with moderate to severe rheumatoid arthritis despite methotrexate therapy [23].

Celltrion reported results of its phase I trial for its rituximab biosimilar (CT-P10) in patients with rheumatoid arthritis. The trial showed no significant statistical differences in pharmacokinetics, efficacy and safety of CT-P10 and its reference product, Roche’s rheumatoid arthritis blockbuster MabThera/Rituxan (rituximab) [24]. Pfizer also reported the ‘similarity’, with respect to in vivo, functional characteristics and pharmacokinetic and pharmacodynamic properties, of their rituximab biosimilar (PF-05280586) compared to MabThera/Rituxan in a phase I trial [25].

In August 2013, US-based Epirus Biopharmaceuticals announced that its biosimilar infliximab candidate (BOW-015) had met study endpoints, supporting the ‘clinical comparability’ of BOW-015 to Remicade (infliximab) in a phase III trial, as measured by the ACR20 response in severe rheumatoid arthritis patients [26]. Pfizer, on the other hand, started a phase I trial for its infliximab biosimilar (PF-06438179) in 2013, which was expected to be completed by September 2013 [23].

Biotechnology giant Amgen has also advanced its biosimilars programme during 2013, starting a phase III clinical trial in July 2013 for a biosimilar version of adalimumab in patients suffering from severe rheumatoid arthritis [27]. Pharma giant Pfizer also started a phase I study for its biosimilar adalimumab candidate (PF-06410293) in June 2013 [28].

Celltrion and Pfizer both presented robust data from their respective biosimilar trastuzumab programmes in June 2013. Celltrion’s phase III data for its biosimilar trastuzumab (CT-P6) showed ‘equivalent efficacy’ of CT-P6 to trastuzumab in terms of overall response rate in patients with HER2+ metastatic breast cancer. Pfizer’s phase I data for its biosimilar trastuzumab (PF-05280014) showed ‘demonstrated similarity’ in terms of pharmacokinetic properties for PF-05280014 compared to Roche’s breast cancer blockbuster Herceptin (trastuzumab) [29]. While injectable generics specialist Hospira presented positive post-marketing data for biosimilar epoetin [30].

Biosimilar deals have also been on the agenda again during 2013. Some notable deals made during 2013 include those of Baxter International (Baxter) with fledgling biotech company Coherus Biosciences, US-based Oncobiologics and Zhejiang Huahai Pharmaceutical, Hospira and NovaQuest Co-Investment Fund I, mAbxience and Brazil-based Libbs Farmacêutica, and Agila Biotech, a subsidiary of India-based Strides Arcolab, and US-based biotech firm Pfenex [3134]. However, others, such as Teva Pharmaceutical Industries and Swiss active pharmaceutical ingredient producer Lonza, have ended their biosimilar collaborations [35].

Guidelines have also been a hot topic for 2013, with Colombia issuing a draft decree for the registration of biologicals, which includes similar biotherapeutic products in January 2013 [36]. Australia’s drug regulatory agency, the Therapeutic Goods Administration (TGA), also published specific guidance for biosimilars on its website in July 2013, which included a section on naming conventions for biosimilars [37].

Meanwhile, India’s drug regulator, the Drugs Controller General of India (DCGI) granted marketing approval for the world first trastuzumab ‘similar biologic’ in November 2013 [38]. While India-based generics company Intas Pharmaceuticals launched its rituximab similar biologic in India in May 2013 [39].

With the number of clinical trials being carried out for biosimilars in 2013, the future looks bright for 2014 in the biosimilars market.

Notes from Editor-in-Chief

It should be noted that for non-inferiority studies failing to find differences larger than a given amount does not necessarily ‘demonstrate equivalence’.

Competing interests: None.

Provenance and peer review: Article prepared based on extensive research; externally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. GaBI Online – Generics and Biosimilars Initiative. EC approves first monoclonal antibody biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/EC-approves-first-monoclonal-antibody-biosimilar
2. GaBI Online – Generics and Biosimilars Initiative. Biosimilar monoclonal antibody approved in Korea [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Biosimilar-monoclonal-antibody-approved-in-Korea
3. GaBI Online – Generics and Biosimilars Initiative. Remsima approved in Colombia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Remsima-approved-in-Colombia
4. GaBI Online – Generics and Biosimilars Initiative. Celltrion applies for biosimilar infliximab approval in Japan [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Celltrion-applies-for-biosimilar-infliximab-approval-in-Japan
5. GaBI Online – Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
6. GaBI Online – Generics and Biosimilars Initiative. Biosimilars applications under review by EMA – 2013 Q4 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: http://www.gabionline.net/Biosimilars/General/Biosimilars-applications-under-review-by-EMA-2013-Q4
7. GaBI Online – Generics and Biosimilars Initiative. J&J adds its opinion to biosimilars naming debate [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/J-J-adds-its-opinion-to-biosimilars-naming-debate
8. GaBI Online – Generics and Biosimilars Initiative. Biosimilars naming debate intensifies [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-naming-debate-intensifies
9. GaBI Online – Generics and Biosimilars Initiative. Calls for biosimilars to have same INN at WHO meeting [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/Calls-for-biosimilars-to-have-same-INN-at-WHO-meeting
10. GaBI Online – Generics and Biosimilars Initiative. Sharing biosimilars substitution information with patients critical [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Sharing-biosimilars-substitution-information-with-patients-critical
11. GaBI Online – Generics and Biosimilars Initiative. US state legislation on biosimilars substitution [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Policies-Legislation/US-state-legislation-on-biosimilars-substitution
12. GaBI Online – Generics and Biosimilars Initiative. EMA issues draft concept paper on comparing quality in biologicals and biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Guidelines/EMA-issues-draft-concept-paper-on-comparing-quality-in-biologicals-and-biosimilars
13. GaBI Online – Generics and Biosimilars Initiative. EGA commends EMA workshop on biosimilars guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/EGA-commends-EMA-workshop-on-biosimilars-guidelines
14. GaBI Online – Generics and Biosimilars Initiative. Canada clarifies regulatory pathway for subsequent entry low molecular weight heparins [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Policies-Legislation/Canada-clarifies-regulatory-pathway-for-subsequent-entry-low-molecular-weight-heparins
15. GaBI Online – Generics and Biosimilars Initiative. FDA finally issues draft biosimilar guidance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Guidelines/FDA-finally-issues-draft-biosimilar-guidance
16. GaBI Online – Generics and Biosimilars Initiative. FDA extends biosimilars deadlines due to US shutdown [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/General/FDA-extends-biosimilars-deadlines-due-to-US-shutdown
17. GaBI Online – Generics and Biosimilars Initiative. FDA issues draft guidance for biosimilar meetings [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-for-biosimilar-meetings
18. GaBI Online – Generics and Biosimilars Initiative. Sandoz starts phase III biosimilar adalimumab trial [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Sandoz-starts-phase-III-biosimilar-adalimumab-trial
19. GaBI Online – Generics and Biosimilars Initiative. Sandoz launches new device for its biosimilar somatropin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Pharma-News/Sandoz-launches-new-device-for-its-biosimilar-somatropin
20. GaBI Online – Generics and Biosimilars Initiative. Non-clinical study shows similarity of biosimilar etanercept [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Non-clinical-study-shows-similarity-of-biosimilar-etanercept
21. GaBI Online – Generics and Biosimilars Initiative. Etanercept biosimilar has comparable pharmacokinetics to Enbrel [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Etanercept-biosimilar-has-comparable-pharmacokinetics-to-Enbrel
22. GaBI Online – Generics and Biosimilars Initiative. Sandoz to start phase III etanercept trial [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Sandoz-to-start-phase-III-etanercept-trial
23. GaBI Online – Generics and Biosimilars Initiative. Trials to start for biosimilar infliximab and etanercept [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Trials-to-start-for-biosimilar-infliximab-and-etanercept
24. GaBI Online – Generics and Biosimilars Initiative. Phase I study shows equivalence of biosimilar rituximab and MabThera [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Phase-I-study-shows-equivalence-of-biosimilar-rituximab-and-MabThera
25. GaBI Online – Generics and Biosimilars Initiative. Non-clinical and phase I clinical assessments show similarity of biosimilar rituximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Non-clinical-and-phase-I-clinical-assessments-show-similarity-of-biosimilar-rituximab/(highlight)/biosimilar
26. GaBI Online – Generics and Biosimilars Initiative. Positive phase III data for Epirus infliximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Positive-phase-III-data-for-Epirus-infliximab-biosimilar
27. GaBI Online – Generics and Biosimilars Initiative. Amgen to start phase III trial for biosimilar adalimumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: http://www.gabionline.net/Biosimilars/News/Amgen-to-start-phase-III-trial-for-biosimilar-adalimumab
28. GaBI Online – Generics and Biosimilars Initiative. Pfizer to start trial for biosimilar adalimumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Pfizer-to-start-trial-for-biosimilar-adalimumab
29. GaBI Online – Generics and Biosimilars Initiative. Robust data for biosimilar trastuzumab programmes presented [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Robust-data-for-biosimilar-trastuzumab-programmes-presented
30. GaBI Online – Generics and Biosimilars Initiative. Positive post-marketing data for biosimilar epoetin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/Research/Positive-post-marketing-data-for-biosimilar-epoetin
31. GaBI Online – Generics and Biosimilars Initiative. Baxter and Coherus to collaborate on biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Baxter-and-Coherus-to-collaborate-on-biosimilars
32. GaBI Online – Generics and Biosimilars Initiative. Huahai and Oncobiologics make biosimilars deal [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Huahai-and-Oncobiologics-make-biosimilars-deal
33. GaBI Online – Generics and Biosimilars Initiative. Biosimilars agreements for Hospira and mAbxience [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Biosimilars-agreements-for-Hospira-and-mAbxience
34. GaBI Online – Generics and Biosimilars Initiative. Agila Biotech and Pfenex make biosimilars deal [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Agila-Biotech-and-Pfenex-make-biosimilars-deal
35. GaBI Online – Generics and Biosimilars Initiative. Teva and Lonza end biosimilars agreement [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Teva-and-Lonza-end-biosimilars-agreement
36. GaBI Online – Generics and Biosimilars Initiative. Colombia issues draft decree for registration of biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Guidelines/Colombia-issues-draft-decree-for-registration-of-biologicals
37. GaBI Online – Generics and Biosimilars Initiative. Naming requirements in Australian biosimilars guidance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Guidelines/Naming-requirements-in-Australian-biosimilars-guidance
38. GaBI Online – Generics and Biosimilars Initiative. Indian regulator approves first trastuzumab ‘similar biologic’ [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Indian-regulator-approves-first-trastuzumab-similar-biologic
39. GaBI Online – Generics and Biosimilars Initiative. Intas launches rituximab ‘similar biologic’ in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 4]. Available from: www.gabionline.net/Biosimilars/News/Intas-launches-rituximab-similar-biologic-in-India

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‘Similar biologics’ approved and marketed in India

There have been established guidelines for approving generic versions of small molecule chemical drugs in India for some time already. However, no specific guidelines for ‘similar biologics’, as the Indian regulatory authorities call these products, have existed in India until recently. This has been the case despite the fact that the requirements for granting regulatory approval for such ‘similar biologics’ required more data than for a simple generic drug application [1].

India announced the release of draft regulatory guidelines for ‘similar biologics’ at the BIO industry conference in Boston, USA, on 19 June 2012, and implemented them from 15 September 2012. The guidelines outline a simple abridged procedure for evaluation of ‘similar biologics’ which have been approved and marketed in India, Europe or USA for more than four years [2].

Biosimilars are firmly established in the EU as copy biologicals with a clear and effective route for approval [3]. It should be noted, however, that ‘similar biologics’ approved and marketed in India have not been subjected to the same rigorous controls and have not necessarily been compared in direct clinical trials to the reference product as is demanded in Europe by the European Medicines Agency. They should not therefore be referred to as biosimilars according to the definition proposed by EMA:

‘A biosimilar is a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise’ [4].

The Central Drugs Standard Control Organization is responsible for the approval, i.e. marketing authorisation of medicinal products, including these so-called ‘similar biologics’, in India.

India has, by far, demonstrated the greatest acceptance of ‘similar biologics’. According to our research at GaBI Online, the first ‘similar biologic’ was approved and marketed in India for a hepatitis B vaccine in 2000. In recent years over 50 biopharmaceutical products have been approved for marketing in India, with more than half of them being ‘similar biologics’ [5], see Table 1.

Competing interests: None.

Provenance and peer review: Article prepared based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. Joshi SR, Biosimilar peptides: need for pharmacovigilance. J Assoc Physicians India. 2011;59 Suppl:44-7.
2. GaBI Online – Generics and Biosimilars Initiative. India releases draft ‘similar biologic’ guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Sep 21]. Available from: www.gabionline.net/Guidelines/India-releases-draft-similar-biologic-guidelines
3. GaBI Online – Generics and Biosimilars Initiative. EMA proposes more precise definition for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Sep 21]. Available from: www.gabionline.net/Biosimilars/Research/EMA-proposes-more-precise-definition-for-biosimilars
4. Wadhwa M, Thorpe R. Terminology for biosimilars-a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):132-4. doi:10.5639/gabij.2012.0103-4.023
5. Jayaraman K. India’s Cipla sets sights on Avastin, Herceptin and Enbrel. Nature Biotechnol. 2010 Sep;28(9):883-4.
6. Mody R, et al. How similar are biosimilars in India? Pharmafocus Asia [monograph on Internet]. c2004–2012 Ochre media; [cited 2012 Sep 21]; Available from: www.pharmafocusasia.com/research_development/blind-comparative-study.html
7. Som N. India on biologics trail. Biospectrum. 13 Feb 2012.

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Copyright © 2013 Pro Pharma Communications International

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Last update: 03/10/2016

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