Submitted: 4 June 2016; Revised: 7 September 2016; Accepted: 15 September 2016; Published online first: 28 September 2016

Introduction

This interactive workshop was held on 2–3 March 2016 at the Hacettepe University in Ankara, Turkey using an almost identical format to what was used in prior educational workshops as reported in GaBI Journal. For more details of methods and case presentations, see the published report of the First Latin American educational workshop on similar biotherapeutic products [1] and the First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars [2].

The workshop was organized in collaboration with the Faculty of Pharmacy, Hacettepe University. Presentations were made by both international speakers as well as local academic faculty, clinicians and Turkish regulators. After the formal presentations (as done in the prior two workshops referenced above), the audience was presented with data for two semi-fictional follow-on biotherapeutic products, one a recombinant human erythropoietin (EPO) and the other a monoclonal anti-TNF antibody. The audience was divided into groups; each of which was asked to discuss specific questions about the potential approval of one of the two proteins under the direction of two to three local, university faculty and regulatory experts. The list of speakers and the slides they presented and the slides used to summarize the quality and clinical trial performance of the two products, are all available on the GaBI Journal website (www.gabi-journal.net/about-gabi/educational-workshops).

Summaries of parallel working group discussions are presented below.

Group 1 and 2 Summary

Groups 1 and 2, who were assigned to evaluate the EPO product, chose to work together rather than separately. The specific questions they were asked and an edited simplified summary of their responses are presented in Table 1.

General summary information of Group 1 and 2 discussions is presented in Table 2.

Discussion/Conclusion of Group 1 and 2

EPO is one of the important glycosylated therapeutic proteins. Glycosylation patterns have effects on immunogenicity and half-life of therapeutic proteins by influencing the active clearance of a protein. Glycosylation is dependent on the number of sialic acid residues attached to the protein molecules. Glycans and sialic acids have effects on receptor binding and serum half-life. Serum half-life of the therapeutic proteins increase when the number of sialic acid residues increases. Glycosylation increases blood half-life but decreases receptor binding.

After manufacturing changes such as manufacturing site and method, the influence of in vitro potency activity should be evaluated. As sialic acid content and lactosamine extension is increased, serum half-life of the product is extended but receptor-binding affinity is decreased. Although the pharmacokinetic profile of the product could be estimated since the serum half-life of the product is known; potency values in patients could not be presumed because of the small differences which have an effect on receptor binding. Some bioassay parameters such as receptor binding and cell proliferation studies should be evaluated for estimating potency values in patients. Sialic acid content differences may increase potency values. Thus, increasing the degree of sialylation and glycosylation decreases the renal clearance rate and can increase EPO in vivo activity.

The structural characteristics of the therapeutic product such as glycosylation and product or process related impurities have effects on quality and immunogenicity of the protein product. Clinical immunogenicity is a key factor to determining safety and efficacy of biosimilars. It is important to note that only clinical studies are appropriate for detecting immunogenicity and for evaluation of clinical safety, at least 12 months of human immunogenicity data should be obtained.

Group 3, 4 and 5 Summary

The three groups who evaluated the IgG1 anti-TNF monoclonal antibody SBP candidate did so separately. The specific questions they were asked followed by the edited, simplified summaries of their individual group responses are presented in Table 3.

Group 4 included further summary information, see Table 4.

Discussion/Conclusion of Group 3, 4 and 5

Despite the large and growing number of products being approved and marketed worldwide as ‘biosimilars’, there continues to be a lack of consensus concerning the best practices for the evaluation, approval, use and post-marketing surveillance of follow-on biologicals. While there were areas of general agreement in the case evaluations done by the participants in this workshop, there were many differences in participants’ responses and opinions from the participants concerning whether these two fictitious follow-on biologicals were qualified to be called biosimilars. This has also been seen in GaBI’s similar workshops.

These differences are likely a reflection of the fact that this is a relatively new area of pharmaceutical science and both the number of products and the information becoming available about the proper definition, approval, monitoring, substitution and switching of follow-on biological products are increasing rapidly. The lack of consensus suggests that academics and regulators, as well as prescribers and patients, need to be provided with the training and unbiased information needed for them to properly approve or regulate, prescribe, or use follow-on biological products, i.e. biosimilars.

Speaker Faculty and Moderators

Speakers
Dr Elwyn Griffiths, DSc, PhD, UK
Professor Dr Ibrahim C Haznedaroğlu, Turkey
Dr Sundar Ramanan, PhD, USA
Dr James S Robertson, PhD, UK
Dr Robin Thorpe, PhD, FRCPath, UK (Chair)
Dr Meenu Wadhwa, PhD, UK
Çisem Başak Budak, Turkey
Professor Philip D Walson, MD, USA/Germany (Co-Chair)

Moderators and Co-moderators

Dr Aydan Eratalay, PharmD, PhD
Bilgen Beldüz, MSc
Dr İsmail Burak Bal
Professor Dr Nazan Bergişadi, PhD
Fikriye Handan Çelikel, MSc
Assistant Professor Dr Devrim Demir Dora, PharmD, PhD
Professor Dr Türkan Eldem, Dr Nat Sci
Professor Dr R Neslihan Gürsoy, PhD
Dr Enes Karabulut, MD
Professor Dr Nefise Ozlen Şahin, PhD
Professor Dr Semra Şardaş
Professor Dr Sevda Şenel, MSc, PhD
Gökçe Yildirim

Editor’s comment

Assistant Professor Dr Devrim Demir Dora of Faculty of Pharmacy/Department of Pharmaceutical Biotechnology at Hacettepe University and Dr Aydan Eratalay from the Turkish Medicines and Medical Devices Agency had read the report, provided the discussion/conclusion of Group 1 and 2 and revised content of Table 2.

Professor Dr Sevda Şenel of Faculty of Pharmacy/Department of Pharmaceutical Technology at Hacettepe University had reviewed Group 3 discussions detailed in Table 3, and confirms that the summary reflects perfectly what has been discussed and decided.

Professor Dr R Neslihan Gürsoy of Faculty of Pharmacy at Hacettepe University had read Group 4 report detailed in Table 3, and commented that it was well prepared.

Professor Dr Türkan Eldem of Faculty of Pharmacy/Department of Pharmaceutical Biotechnology at Hacettepe University had reviewed Group 5 discussions detailed in Table 3 and made a few updates.

Acknowledgements

The Generics and Biosimilars Initiative (GaBI) wishes to thank Professors Bülent Gümüşel and Neslihan Gürsoy of the Hacettepe University for their strong support through the offering of advice and information towards the development and preparation of this interactive workshop.

The authors would like to acknowledge the help of all the workshop speaker faculty and participants, each of whom contributed to the success of the workshop and the content of this report, as well as the support of the moderators and co-moderators: Dr Aydan Eratalay, Bilgen Beldüz, Dr İsmail Burak Bal, Professor Dr Nazan Bergişadi, Fikriye Handan Çelikel, Assistant Professor Dr Devrim Demir Dora, Professor Dr Türkan Eldem, Professor Dr R Neslihan Gürsoy, Dr Enes Karabulut, Professor Dr Nefise Ozlen Şahin, Professor Dr Semra Şardaş, Professor Dr Sevda Şenel, Gökçe Yildirim, in facilitating meaningful discussion during the parallel case study working session, presented the discussion findings at the workshop and contributed in the finalization of this Meeting Report.

Competing interests: The workshop was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.

Provenance and peer review: Commissioned; internally peer reviewed.

Co-author

Robin Thorpe, PhD, FRCPath
Deputy Editor-in-Chief, GaBI Journal

References
1. Walson PD, Thorpe R. First Latin American educational workshop on similar biotherapeutic products, Mexico City, Mexico, 20 January 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):143-8. doi:10.5639/gabij.2015.0403.031
2. Walson PD, Thorpe R. First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars, Dubai, United Arab Emirates, 1 September 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):173-7. doi:10.5639/gabij.2015.0404.039

Disclosure of Conflict of Interest Statement is available upon request.

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