Access to safe and effective biopharmaceuticals

Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD

Abstract:
Comment on the Letter to the Editor by Professor Abdol Majid Cheraghali: Access to alternative biopharmaceuticals in low- and middle-income countries, published in GaBI Journal, 2014;4(3):164-5.

Submitted: 7 June 2015; Revised: 8 June 2015; Accepted: 8 June 2015; Published online first: 22 June 2015

In the above Letter to the Editor of GaBI Journal, it is concluded that although biosimilars offer potentially increased global patient access to biopharmaceuticals due to lowering of prices, this may be problematic in low- and middle-income countries primarily due to local resource limitations and lack of experience.

The author questions the relevance of the World Health Organization (WHO) and European Medicines Agency (EMA) guidance and the applicability of the similarity/comparability concept for development of biosimilars in low- and middle-income countries. He considers that these processes are ‘not feasible’ in such countries and elaborates possibilities for regulatory procedures which could be adopted by them for approval of follow-on biological products, thus, obviating the extensive comparability studies as required by WHO, EMA and many other guidelines. We think that this proposal needs much care and consideration before it is seriously considered. The reasons for this are outlined below.

As the letter states, several follow-on biological products are marketed worldwide. As has been discussed previously, biosimilars approved in the European Union are safe and efficacious. However, some products marketed elsewhere are not. These latter products are not biosimilars as there is no evidence that they have been approved using the biosimilarity approach described in the WHO guideline. Furthermore, evaluation of product characteristics pertaining to their quality has clearly demonstrated that these products differ from the reference product [1, 2]. The letter also states that ‘Most of the guidelines published for regulation of alternative biopharmaceuticals, including WHO guidelines, rely on head-to-head comparative clinical studies for proven similarity between innovator products and alternative biopharmaceuticals.’ Indeed, use of this approach, i.e. showing that the biosimilar and the reference product have very similar safety and efficacy, guarantees the safety and efficacy of true biosimilars as substantiated by the proven excellent clinical record of biosimilars approved using this regulatory process [3, 4]. Additionally, this approach allows extrapolation of the product for various therapeutic indications without the need for clinical trials in each indication providing that the therapeutic acts via the same receptor and the mechanism of action remains the same in different indications [5]. The author should also note that despite 10 years of experience with biosimilars, comparative clinical data is still required by EMA in the revised guideline on non-clinical and clinical issues to ensure that the ‘claimed’ biosimilar has a similar efficacy and safety profile to the reference product [6].

The letter describes the process for marketing authorization approval used in low- and middle-income countries as relying on ‘a loosely designed and practised clinical study’. It is acknowledged that it is now well established that ignoring the need for appropriate assessment of quality, preclinical and clinical performance of biotherapeutics (including biosimilars) can lead to serious clinical problems: a good example of this is the high incidence of PRCA (pure red cell aplasia) development following treatment with the many EPO (erythropoietin) products which are approved in Thailand [7, 8]. In any case, quality assessment, which is the foundation of the biosimilarity exercise, is normally cheaper than conducting clinical trials and so the reason for relying solely on clinical assessment seems illogical. The letter acknowledges that ‘The manufacturing of biopharmaceuticals is somewhat different to that for small molecule chemical medicines, and the procedure is much more sensitive to change in the production process and even environmental factors’. Nevertheless, this again questions the wisdom of not conducting a quality assessment of non-innovator products of any type.

The letter considers that historical experience gained with innovator products can be used to assess possible problems with follow-on products. Although such information (when reliable) can provide a general guide for expected problems, it cannot ensure appropriate clinical safety and efficacy for a new product. This has to be assessed directly, using a proven pathway.

In addition, shortened regulatory processes are proposed involving no head to head clinical trial, no trial at all and reliance on approval followed by phase IV assessment by regulatory agencies. How this latter approach could excuse the pharmaceutical company developing the product from its obligation to guarantee safety and efficacy of their product is not explained nor is how the previously mentioned lack of resources and expertise in low- and middle-income countries would allow it. Although the author is in favour of promoting access to biotherapeutic products (which is laudable), the approaches outlined are not akin to the biosimilar philosophy and also not aligned with the WHA resolution (WHA67.21) ‘Access to biotherapeutic products including similar biotherapeutic products and ensuring their quality, safety and efficacy’.

A request is made in the letter for a ‘more pragmatic’ guideline (perhaps from WHO or regulatory authorities), presumably describing some form of abbreviated procedure for regulatory approval of follow-on products. But, considering the above, how is this possible if safety and/or efficacy are not to be compromised? WHO already has current guidelines for Similar Biotherapeutic Products (SBPs) [9] and Biotherapeutic Products (BTPs) [10] which should be applicable to all biotherapeutic products. In a recent WHO Informal Consultation on the amendment for similar biotherapeutic products of monoclonal antibodies (April 2015) in Geneva, Switzerland, the WHO SBP guideline was reviewed and the consensus opinion was that it did not require revision and should be implemented globally. In addition, WHO is in the process of providing guidance on re-evaluation of products that are currently marketed, but have not been tested thoroughly or do not fulfil current international regulatory standards. This again suggests that existence of low regulatory standards is considered a global problem; reducing such standards has been identified as a threat to public health.

It is clearly the prerogative of regulatory agencies in low- and middle-income countries to adopt appropriate procedures for approval of biotherapeutic products. These need to take account of all relevant factors including clinical safety and efficacy. But if they decide to approve follow-on products by procedures which do not comply with the WHO SBP guideline, then these should not be called biosimilars or SBPs. They should be named in accordance with the process used for their approval.

Competing interest: None.

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

Co-author

Meenu Wadhwa, PhD, Cytokine and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK

References
1. Meager A, Dolman C, Dilger P, Bird C, Giovannoni G, Schellekens H, et al. An assessment of biological potency and molecular characteristics of different innovator and noninnovator interferon-beta products. J Interferon Cytokine Res. 2011;31(4):383-92.
2. Schellekens H. Biosimilar epoetins: how similar are they? Eur J Hosp Pharm. 2004;10(3):43-7.
3. Thorpe R, Wadhwa M. Terminology for biosimilars – a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3):132-4. doi:10.5639/gabij.2012.0103-4.023
4. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7.
5. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6.
6. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues [homepage on the internet]. 2014 [cited 2015 Jun 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf
7. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, Jootar S, Intragumtornchai T, Tungsanga K, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011;80(1):88-92.
8. Shin SK, Moon SJ, Ha SK, Jo YI, Lee TW, Lee YS, et al. Immunogenicity of recombinant human erythropoietin in Korea: a two-year cross-sectional study. Biologicals. 2012;40(4):254-61.
9. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPS). Annex 2, WHO Technical Report Series No 977 [homepage on the Internet]. [cited 2015 Jun 8]. Available from: http://www.who.int/entity/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1; 2009
10. World Health Organization. Guidelines on the quality, safety, and efficacy of biotherapeutic products prepared by recombinant DNA technology. Annex 4, WHO Technical Report Series No 987 [homepage on the Internet]. [cited 2015 Jun 8]. Available from: http://apps.who.int/medicinedocs/documents/s21514en/s21514en.pdf

Author for correspondence: Robin Thorpe, PhD, FRCPath, Deputy Editor-in-Chief, GaBI Journal

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.

Source URL: http://gabi-journal.net/access-to-safe-and-effective-biopharmaceuticals.html


Biosimilar monoclonal antibodies approved for use in the EU

Abstract:
Two biosimilar TNF-alfa monoclonal antibody (mAb) products were approved for clinical use in the European Union on 10 September 2013, following a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) in July 2013. The products, with trade names Remsima and Inflectra (INNs infliximab) contain an identical mAb. This approval shows the feasibility of using the biosimilar pathway for mAbs and paves the way for further biosimilar mAb products.

Submitted: 9 January 2014; Revised: 27 January 2014; Accepted: 28 January 2014; Published online first: 10 February 2014

Monoclonal antibodies (mAbs) have great potential for clinical use in vivo. Their specificity and ability to be produced to bind to almost any antigen of clinical interest has established them as potentially probably the largest class of biotherapeutics. Many are now approved for clinical use, many more are in various stages of clinical development and some are considered ‘blockbuster’ high income products. It would therefore seem reasonable to develop biosimilar mAbs, at least for the higher-usage products.

While it was previously considered that the molecular complexity and relatively large size of mAbs may limit the feasibility of using the European Union (EU) biosimilar approach for them [1], this has now been proven to be not the case, as the first two biosimilar mAb products were approved for use in the EU by the European Commission on 10 September 2013, following a positive opinion in July 2013 by the Committee for Medicinal Products for Human Use (CHMP). The two products, with trade names Remsima and Inflectra have used the TNF-alpha mAb Remicade as the reference product and the marketing authorizations are held by Celltrion and Hospira, respectively. All three mAbs have the same INN (infliximab), which reflects their similarity. However, the biosimilars do show some differences in glycosylation and so, according to the INN ‘rules’ a Greek letter could have been added as an identifier as a second word of the INN, but this option was not considered. The CHMP view was that the small differences in glycosylation were not clinically significant, based on the clinical trial data.

Both Remsima [2] and Inflectra [3] contain an identical mAb and are the same in their pharmaceutical form, strength, composition and route of administration but the packaging size varies.

Despite the approval of both biosimilar mAbs in September 2013, a Remicade patent extension has prohibited their sale in the EU although not elsewhere (Remsima has been marketed in South Korea for some time post approval as a biosimilar by the (then) Korean FDA in July 2012). Resolution of the patent issues will allow the biosimilars to be marketed in the EU later this year or in 2015; precise dates for this will differ between states and also could be affected by other considerations, such as marketing factors.

As per EU biosimilar requirements, the approval application included a detailed and thorough characterization of the mAb and an exhaustive quality comparison of the biosimilar with the reference product using state-of-the art methods. This was complemented by comparative non-clinical and clinical studies in a sensitive model to establish and confirm clinical biosimilarity. This comparability exercise data taken together provided an overall ‘proof’ of biosimilarity and assurance that the safety and efficacy profile of the biosimilar versions matches that of the reference product. This is stressed in the European Public Assessment Report (EPAR) for Remsima [2] which states ‘The Agency’s Committee for Medicinal Products for Human Use (CHMP) decided that, in accordance with EU requirements, Remsima has been shown to have a comparable quality, safety and efficacy profile to Remicade’. Therefore, the CHMP’s view was that, as for Remicade, the benefit outweighs the identified risks. The Committee recommended that Remsima be approved for use in the EU for all therapeutic indications of Remicade. Similar is the case for Inflectra [3].

The very important and often misunderstood issue of clinical comparability is also addressed by quoting data in the EPAR [2], i.e. ‘Remsima was studied to show that it is comparable to the reference medicine, Remicade. Remsima was compared with Remicade in one main study involving 606 adults with rheumatoid arthritis. Patients received either Remsima or Remicade in addition to methotrexate for 30 weeks. The main measure of effectiveness was the change in symptoms (measured by ACR20). After 30 weeks of treatment Remsima was as effective as Remicade, with around 60% of patients responding to treatment with either medicine’. The EPAR also contains statements relating to other key similarities found for the biosimilar and reference product, e.g. pharmacokinetics. No unexpected safety issues occurred, and immunogenicity was very similar to that observed for Remicade. For further information, see the EPARs at www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000240/human_med_001023.jsp&mid=WC0b01ac058001d124

It should be stressed that Remsima and Inflectra have been thoroughly characterized to show their biosimilarity to Remicade. Unfortunately, this is not the case for what are claimed to be ‘biosimilar mAbs’ marketed in some non-EU countries, for example, China and India. This problem has been highlighted before [4], but is still continuing as reports describing limited assessment of poorly compared products are still referring to these products as ’biosimilars’ although they are clearly not such according to EU (and WHO) definitions [5].

The EU approval of the two biosimilar mAb products not only demonstrates the feasibility of using the biosimilar pathway for relatively large, complex molecules, but also sets a precedent for other biosimilar mAb products to follow. We should expect several more biosimilar mAbs in the near and medium future. Perhaps a biosimilar trastuzumab will be next?

But the real challenge for biosimilar mAbs, at least in the EU will be market penetration. Pricing and uptake of Remsima and Inflectra throughout the EU will be interesting from this important perspective. Equally, improved communication with physicians [6], payers and patients on the rigorous regulatory approval process should facilitate an increase in the uptake of these types of products.

Competing interests: None.

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

Co-author

Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

References
1. Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nat Biotechnol. 2008;26(9):985-90.
2. European Medicines Agency. Assessment report – Remsima [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jan 27]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf
3. European Medicines Agency. Assessment report – Inflextra [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jan 27]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf
4. Thorpe R, Wadhwa M. 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. Tan Q, Guo Q, Fang C, Wang C, Li B, Wang H, et al. Characterization and comparison of commercially available TNF receptor 2-Fc fusion protein products. MAbs. 2012;4:761-74.
6. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7.

Author for correspondence: Robin Thorpe, PhD, Deputy Editor-in-Chief, GaBI Journal

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.

Source URL: http://gabi-journal.net/biosimilar-monoclonal-antibodies-approved-for-use-in-the-eu.html


New CHMP guideline on immunogenicity of monoclonal antibodies

Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD

Abstract:
The importance of monoclonal antibodies as a product class and the challenge of assessing unwanted immunogenicity for these products have prompted the drafting of a new CHMP (Committee for Medicinal Products for Human Use) guideline. The ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ is intended as an annex to the existing general immunogenicity guideline. This guidance in conjunction with other relevant CHMP guidelines should assist manufacturers and regulators who are involved with producing or assessing marketing authorization applications for monoclonal antibody products.

Submitted: 4 February 2013; Revised: 6 February 2013; Accepted: 7 February 2013; Published online first: 12 February 2013

Unwanted immunogenicity remains a major concern for biological products including biosimilars. Assessing the immunogenicity of biologicals and the possible clinical consequences of this is a considerable challenge and requires carefully planned, prospective immunogenicity studies, conducted using appropriate patient groups. Regulatory guidance on this has been published by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) (Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins; EMEA/CHMP/BMWP/14327/2006). This guideline, which came into effect in 2008, has been used by manufacturers of biologicals and regulators especially at the marketing authorization stage of regulatory product approval. Although it has been generally well received, one criticism of it is that it is ‘too general’ and does not provide specific guidance for particular products or classes of products. The latter point is indeed true, as the guideline was intentionally drafted to provide general guidance relating to all biological products. Drafting guidelines dealing with immunogenicity issues for specific products is possible, but has been considered unnecessary or even undesirable. It would be a major task to produce specific guidelines covering the very wide range of biological products now being produced or in development and there would be much overlap in the content of many of the specific guidelines as several aspects of unwanted immunogenicity are common to all biologicals. But, in some cases there are issues that affect some products more than others or are different for different biologicals. Normally, this has to be dealt with on a case-by-case basis. However, in some cases for specific products or product classes, generalities pertaining to their immunogenicity may apply, which may merit the preparation of specific immunogenicity guidelines. One such large class of products is monoclonal antibodies (mAbs). This is clearly a very important class of biotherapeutics and in vitro diagnostics, for which there are several approved products in the EU and elsewhere; many more are in development.

In view of this situation, and following internal and external consultation, the decision was taken to draft a mAb specific CHMP immunogenicity guideline. This guidance, titled ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ (EMA/CHMP/BMWP/86289/2010) has now been adopted by CHMP (again following public consultations) and came into effect in December 2012. It is intended as an addendum to the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’ (EMEA/CHMP/BMWP/14327/2006), i.e. that it should be read in conjunction with the general guideline. The new guideline includes sections addressing problems experienced with screening and confirmatory assays used in assessing immunogenicity of mAbs (assays for antibody detection, presence of mAb product in samples for analysis, confirmatory assays and controls), assessment of the neutralising capacity of antibodies induced against mAbs and considerations on immunogenicity risk management of mAbs (risk identification, risk management and risk monitoring and mitigation). The guideline concentrates on specific issues, problems and technicalities that relate to mAbs and products that have similarities to mAbs, such as IgFc fusion proteins. However, some parts of the guideline contain useful information that can also apply to other biologicals. The new immunogenicity of mAbs guideline will apply to all mAbs, including biosimilar mAbs, but treats biosimilars as just a subclass of biologicals (which they clearly are) with no specific requirements from the immunogenicity perspective. This follows the approach taken in the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’.

However, immunogenicity assessment for biosimilars does differ in one important aspect from immunogenicity assessment of stand-alone biologicals, as comparative immunogenicity, which is an essential element of the comparability studies, has to be assessed for the candidate biosimilar and the innovator (reference) product. Non-clinical and clinical issues relating to biosimilar mAbs are addressed in another new guideline, ‘Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues’ (EMA/CHMP/BMWP/403543/2010); which includes sections that address these aspects of immunogenicity for biosimilar mAbs. This guideline is specific to the mAb product class and therefore needs to be read alongside the ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’. Of note, the biosimilar mAb guideline does not reflect on the quality aspects of mAbs as a guideline dealing with this particular aspect is already in place (Guideline on development, production, characterization and specifications for monoclonal antibodies and related products; EMEA/CHMP/BWP/157653/2007) although this does not include any considerations for specific assessment of immunogenicity of biosimilars (this was not thought to be necessary at the time when the guideline was drafted). From the immunogenicity perspective, it is clear that the methodology and strategy for assessment of immunogenicity of biosimilar products including mAbs needs careful evaluation to ensure that this is appropriate for the required comparative assessment. In particular, it is important to ensure that screening procedures identify all patients who develop antibodies against the product that they receive, i.e. the candidate biosimilar or the reference product. This implies that at least screening assays need to be tailored to include the use of the biosimilar and the reference product as antigens (usually conducted as separate assays) and samples from treated patients are screened against the antigen relating to the product that they received. If the trials are double blind (as is normally required for mAbs), then this means that samples will have to be screened against both antigens, as the identity of the product that the patients have received is unlikely to be known at the time of screening. If this strategy is not adopted, it is possible that false negative results may be generated for some patients as one or more epitopes present on the biosimilar and reference products may not be shared. This aspect of immunogenicity assessment strategy is likely to receive considerable attention as more experience is gained with immunogenicity assessment of biosimilar products including mAbs. It is also important to understand the underlying causes of immunogenicity when comparing the incidence of immunogenicity. For example, it may be that differences observed with immunogenicity between a candidate biosimilar and the reference product are due to differences in impurity profiles due to a change in the expression system.

The new immunogenicity of monoclonal antibodies guideline stresses the importance of risk assessment for immunogenicity management, but emphasises the need to take account of the numerous factors that may contribute to immunogenicity, e.g. the production system used, the patient population treated, the clinical indication(s) selected for treatment and the antigen target of the mAb. It is not possible to assign a single ‘risk level’ for mAbs as a product class, as each product needs to be assessed on a case-by-case basis, taking account of all the risk factors.

For patients

Monoclonal antibody products are potentially very valuable medicines and several are approved for the treatment of a range of clinical problems. Many more such products are in development. Unwanted immunogenicity associated with mAb products can be a problem, occasionally resulting in adverse effects and more often a reduction in clinical efficacy. The new guideline described in this article will help manufacturers of mAb products in assessing unwanted immunogenicity of mAbs and will also aid regulators in their evaluation of mAb products for approval for marketing.

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

Co-author

Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

Author for correspondence: Robin Thorpe, PhD, FRCPath, Head – Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 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.

Related article
ICH Q11: development and manufacture of drug substances–chemical and biotechnological/biological entities

Source URL: http://gabi-journal.net/new-chmp-guideline-on-immunogenicity-of-monoclonal-antibodies.html


Terminology for biosimilars–a confusing minefield

Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD

Abstract: 
Biosimilars are firmly established in the EU as copy biologicals with a clear and effective regulatory route for approval. Unfortunately, inconsistency in nomenclature for biosimilars has caused confusion. This problem of terminology has been the subject of a recent publication. The confusion is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions in published reports. Several examples of this have occurred, some of which are discussed below. The definitions provided should be adopted for clarity in the future.

Submitted: 26 June 2012; Revised: 2 July 2012; Accepted: 3 July 2012; Published online first: 3 July 2012

Biosimilars are now firmly established in the EU as copy biologicals with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biological products.

The comparability studies required for comparing the innovator (reference) product and the potential biosimilar product are crucial for the regulatory process and guarantee the quality and clinical performance of the biosimilar. Clear guidelines have been produced by the Committee for Medicinal Products for Human Use and its working parties, describing the desired criteria including quality, non-clinical and clinical studies needed for biosimilars and requirements for their regulatory approval in the EU [15, 20]. The comparability of quality aspects required is significant and some data from such studies have been partially published [6, 7]. To date, 14 marketing authorisations have been approved for biosimilars in the EU and many more are in the pipeline.

Outside the EU, several countries have adopted an identical or similar regulatory approach to the EU for approval of biosimilars, e.g. Australia, Canada, Japan. In addition, the World Health Organization (WHO), with the aim of achieving harmony in regulations and increasing access to safe medicines globally has produced a guideline [8] for evaluation of ‘similar biotherapeutic products’ (effectively biosimilars) which proposes a very similar approach to that described in the EU guidelines [13].

Unfortunately, inconsistency in nomenclature used for biosimilars has led to confusion in referring to some products. Thus the terms ‘follow-on biologic’, ‘subsequent entry biologic’, ‘similar biotherapeutic product’, ‘similar biological medicinal product’, ‘biogeneric’, ‘me-too biologic’, ‘non-innovator biologic’ have all been used to describe biosimilars. An even greater problem is that all of these terms have in some cases been used to refer to products which are not biosimilars according to the EU/WHO definitions and have not been evaluated using the comparability approach which is essential if the guidelines are followed. This problem of terminology and its implications has been the subject of a recent publication by Weise et al. [9], and this paper also recommends the use of more precise terminology for biosimilars (and non-biosimilars) to attempt to clarify the confusing situation.

The confusion over terminology is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions which arise from misleading published reports on apparent problems with ‘biosimilars’. Several examples of this have already occurred, some of which are discussed below.

A case of pure red cell aplasia (PRCA) in an end-stage renal disease patient associated with induction of antibodies to administered erythropoietin (EPO) was described in India [10]. The patient had received the EPO product Wepox (Wockhardt Limited, India) which is referred to as a ‘follow-on’ product. In the paper the authors state that ‘in Europe, follow-on EPOs are also referred to as biosimilar EPOs’. However, there is no evidence that this product has been approved using the comparability approach required in the EU for biosimilarity and described in the WHO and other guidelines. This is in fact unlikely as the Indian regulatory process at that time did not include biosimilars (or follow-on products) and approved non-innovator products based on a stand-alone system [11]. Thus the product Wepox which is not a biosimilar and should not be described as such as this clearly misleads the reader by using incorrect terminology.

In some cases, the type of product referred to in studies is unclear. An example of this is a report [12], describing two cases of antibody mediated PRCA in South Korea which developed following treatment with a locally produced EPO (Epokine, CJ Corp, Korea) or a mixture of three such products and an innovator product. The procedure adopted for approval of the locally produced EPOs is not reported, but is unlikely to be via the biosimilar route as the Korean biosimilar guideline was produced only recently. The Korean regulatory process however includes both comparative (biosimilar) and non-comparative procedures, and use of correct terminology in publications would avoid ambiguity and misunderstanding.

Another serious example of misuse of terminology in a publication appeared with the alarming title ‘Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies’ [13].This paper describes loss of response to EPO in a number of patients being treated with what are called biosimilar EPOs in Thailand. These products were produced in Argentina, China, India and South Korea, and 14 different such products were approved for use in Thailand. Laboratory evaluation showed 23 of these patients to be EPO antibody positive, all of whom progressed to PRCA. However, none of these products were really biosimilars as all were approved using the process employed for chemical generics, i.e. no comparison with originator product was conducted. The editor of the journal in which this report appeared seems to have noted a potential problem with terminology for biosimilars as an editor’s note appears in the paper providing an explanation of the term. Unfortunately, this simply states that the term ‘biosimilar’ is applied to subsequent versions of products that have been approved in a given country, and not that the approval process should involve a comparative assessment of the ‘biosimilar’ with the innovator product. This report is particularly misleading as the implication is that biosimilar EPOs are more likely to cause antibody induction and PRCA than innovator products which is not shown in the study as none of the products used were biosimilars in the sense of correct terminology.

It is particularly important that correct terminology for biosimilars is used in reviews highlighting their potential importance. However, this is often not done. For example, in a recent review of the current development of ‘biosimilars’ in India [14], a number of products produced and sometimes approved in India, including filgrastim, epoetins, interferons and a monoclonal antibody are listed as biosimilars even though the limitations described for the above mentioned Indian Wepox/PRCA case also apply to these products. Again, this is a clear misuse of terminology.

Granulocyte colony-stimulating factor (G-CSF) has been widely used clinically and several biosimilar G-CSF products have been approved for marketing. There has been considerable discussion of the pros and cons of biosimilar G-CSFs in the literature. However, in many cases, it is not clear whether products referred to as biosimilars are really biosimilars. For example, in a review of the use of G-CSF for mobilization of stem cells [15], an Argentinean product (Neutromax) is described as a biosimilar although it has not been approved using the biosimilar procedure [16]. This is particularly confusing as the review also discusses ‘real’ biosimilars approved in the EU using the correct regulatory system. This confusion could be easily avoided by only using the term ‘biosimilar’ for products approved using the correct procedure and referring to other subsequent entry products as ‘non-innovator products’.

A glaring example of misleading terminology is evident in a recent publication [17], from Iran describing a comparative study in multiple sclerosis patients receiving Avonex (an innovator beta interferon (IFN) product) and Cinnovex (a locally produced non-innovator beta IFN product). Both products are referred to as ‘biosimilar forms’ of beta IFN and the title refers to ‘biogeneric/biosimilar IFN beta-1a’. Cinnovex is clearly designated a biosimilar in the report, but no reference is made in the text to what the term ‘biogeneric’ as used in the title means. No mention of any comparative quality evaluation between Cinnovex and an originator product is provided and so it is unlikely that it is a true biosimilar.

The above are only a few of many similar examples in the literature. The current situation is very misleading and alarming for healthcare professionals who could be easily misinformed concerning the safety (including the important issue of unwanted immunogenicity [5]) of biosimilars. They may be dissuaded from prescribing biosimilars because of a false concern for patient safety.

It has been shown that the quality of different non-innovator/copy products can vary significantly and even different batches of what appears to be the same product can differ, with implications for both efficacy and safety [10, 18, 19, 20]. It is therefore imperative that clear terminology is used to accurately describe the nature and particularly the regulatory procedure used for particular biologicals.

In order to avoid future problems with terminology for biosimilars and non-biosimilars, it is emphatically proposed that the recommendations expressed in the Weise et al. publication [9], are followed. The definitions provided in the publication for the terms ‘biosimilar’ and ‘non-innovator biologic’ should be adopted in future for accurately referring to the nature of relevant products.

These measures should hopefully lead us out of the confusing and often misleading minefield with terminology for biological products which we are in at present.

For patients

Patient access to biosimilars is an important factor in economic health care. But this requires assurance that biosimilars are safe and efficacious. This is dependent on a clear definition of what is, and is not, a biosimilar. Unfortunately, inconsistency in nomenclature for biosimilars has caused confusion and this problem of terminology has been the subject of a recent publication. The confusion is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions in published reports. The definitions provided here should be adopted for clarity in the future, so that healthcare professionals and patients are clearly aware of the regulatory processes used to approve the products they are using.

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

Co-author

Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

References
1. European Medicines Agency [homepage on the Internet]. Guideline on similar biological medicinal products (2005) [cited 2012 Jul 2]. Available from: http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf.
2. European Medicines Agency [homepage on the Internet]. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 2012 May 24 [cited 2012 Jul 2] Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127960.pdf
3. European Medicines Agency [homepage on the Internet]. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (2006) [cited 2012 Jul 2]. Available from: http://www.emea.europa.eu/pdfs/human/biosimilar/4283205en.pdf
4. European Medicines Agency [homepage on the Internet]. Guidance on similar medicinal products containing recombinant erythropoietins 2006 [cited 2012 Jul 2]. Available from: http://www.emea.europa.eu/pdfs/human/biosimilar/9452605en.pdf
5. Wadhwa M, Thorpe R. The challenges of immunogenicity in developing biosimilar products. IDrugs. 2009;12:440-4.
6. Brockmeyer C, Seidl A. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. Eur J Hosp Pharm Prac. 2009;15(2):34-40.
7. Skrlin A, Radic I, Vuletic M, Schwinke D, Runac D, Kusalic T, Paskvan I, Krsic M, et al. Comparison of the physicochemical properties of a biosimilar filgrastim with those of reference filgrastim. Biologicals. 2010;38:557-66.
8. World Health Organisation [homepage on the Internet]. Expert Committee on Biological Standardization. Guidelines on evaluation of similar biotherapeutic products (SBPs). 2009 Oct 19-23. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22 APRIL2010.pdf
9. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Narayanan G, Heim HK, Heinonen E, et al. Biosimilars-why terminology matters. Nat Biotechnol. 2011;29:690-3.
10. Keithi-Reddy SR, Kandasamy S, Singh AK. Pure red cell aplasia due to follow-on epoetin. Kidney Int. 2008;74:1617-22.
11. Malhotra H. Biosimilars and non-innovator biotherapeutics in India: an overview of the current situation. Biologicals. 2011;39:321-4.
12. Yang J, Joo KW, Kim YS, Ahn C, Han JS, Kim S, Lee JS. Two cases of pure red-cell aplasia due to anti-erythropoietin antibodies. J Nephrol. 2005;18:102-5.
13. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, Jootar S, Intragumtornchai T, Tungsanga K, Teerapornlertratt T, Lumlertkul D, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011;80:88-92.
14. Rathore A. Development and commercialization of biosimilars in India. BioPharm International, 2011;Nov 1;24(11):36-40.
15. Shaw BE, Confer DL, Hwang WY, Pamphilon DH, Pulsipher MA. Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematologica. 2011;96:942-7.
16. Ferro HH, Juni M, Bello R, Vidal A, Diez RA, Pavlovsky S. Utilization study of filgrastim (Neutromax) during autologous haematopoietic precursor transplantation for myeloma and lymphoma patients. Transfus Apher Sci. 2009;41:87-93.
17. Nafissi S, Azimi A, Amini-Harandi A, Salami S, Shahkarami MA, Heshmat R. Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: A double blind randomized clinical trial. Clin Neurol Neurosurg. 2012 Sep;114(7):986-9. Epub 2012 Mar 18.
18. Meager A, Dolman C, Dilger P, Bird C, Giovannoni G, Schellekens H, Thorpe R, Wadhwa M. An assessment of biological potency and molecular characteristics of different innovator and noninnovator interferon-beta products. J Interferon Cytokine Res. 2011;31:383-92.
19. Schellekens H. Biosimilar epoietins: how similar are they? Eur J Hosp Pharm. 2004;3:243-7.
20. Declerck P. Biologicals and biosimilars: a review of the science and its implications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):13-6. doi:10.5639/gabij.2012.0101.005

Author for correspondence: Robin Thorpe, PhD, FRCPath, Head – Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

Disclosure of Conflict of Interest Statement is available upon request.

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.

Related article
Assessing biosimilarity and interchangeability of biosimilar products under the Biologics Price Competition and Innovation Act

Source URL: http://gabi-journal.net/terminology-for-biosimilars-a-confusing-minefield.html


Generics and Biosimilars Initiative (GaBI)
Tel: +32 474989572 | Fax: +32 14 583 048