25 – 27 OCTOBER, 2018 Budapest, Hungary

Biosimilars & Nanosimilars: Chalenges and Future Perspectives – note from Annual Professional Forum at Accelsiors Ltd, Budapest

There were two short courses, both focusing on the problem of multiplicity in PK equivalence studies of biosimilars. Both pointing out that although there is a detailed guideline available for the univariate handling of PK parameters, the questions of multiplicity and the handling of missing data (mainly data below the limit of quantification) are still open. Solutions are complicated and a good guideline avoiding the cookbook style would be needed, but this may take years. When it arrived to real examples it was really interesting to see that the two different theoretical solutions proposed, based on different principles (Thomas Jaki’s and Philip Pallmann’s method based on joint confidence regions [for which an R package jocre was developed by Philip Pallmann], and Ludwig Hothorn’s method of a union-intersection test [UIT]) approach [more precisely UIT for testing multiple endpoints and multiple treatments, and intersection-union test for the two one-sided tests applied to each single parameter]) led to very similar results at the end.

Day 2: Symposium – Clinical studies and regulatory questions

On the next day various problems related to biosimilar development were discussed. We got update on the bioequivalence of highly variable drugs (László Endrényi), and on development strategies of recently approved biosimilars in Europe (Johanna Mielke).

The regulatory keynote presentation was held by Andrea Laslop, and she gave some very interesting examples of difficult decision when the prescriptions of the guideline could not be kept entirely (e.g. confidence interval slightly exceeding the pre-defined margins which could be attributed to recent manufacturing changes of the originator, or slightly higher ADA incidence which did not translate into meaningful differences in clinical efficacy) but still a positive decision was made based on the totality of evidence. All these lead to the conclusion that the assessment of biosimilarity in critical quality attributes should be strengthened in the future (new statistical approaches to be defined), and tailoring of clinical evidence is needed. Gyurasics Ágnes presented some challenging issues in extrapolation of totality of evidence to pediatric indications in case of biosimilars.

Continuing with a problem similar to the question raised by Andrea Laslop (i.e. how to take into account changes in the manufacturing changes of the originator), Heike Woehling analyzed cases where differences between immunogenicity results were partly attributable to the increased assay sensitivity. Common statistical tests do not take into account changes occurred in assay methodology, therefore estimates of the same parameter obtained at different time points are difficult to be compared. However, as Julia Singer pointed out, statistical methods to adjust the observed proportions for a known sensitivity and specificity are known (the first such method was published by Rogan and Gladen, 1978).

Although in different ways, all the presentations addressed somehow the question of what the future may/might bring to us. For instance, Johanna Mielke presented a hybrid Bayesian-frequentist statistical method to incorporate historical information on the reference product in clinical studies to assess biosimilarity. Emmanuelle Vincent shared her experience about the opportunities and limitations of a blinded sample size reassessment in some clinical studies. In the future the role of PD markers is expected to increase, and skipping clinical efficacy trials in the development of biosimilars will be chosen more and more often.

As a kind of preambulum to the third day of the forum which was dedicated to nanosimilars, János Szebeni delivered a presentation on animal models of immunogenicity and immune toxico-equivalence testing of nano-biopharmaceuticals.

In the closing part of the second day there was an animated panel discussion led by Helmut Schuetz. Various topics were raised, here we mention only some of them: the inadequacy of the simple two-by-two cross-over design to separate different effects like period, sequence, carry-over; the criterion of equivalence in mean is required which later might be incorrectly interpreted as equivalence in distribution.

Day 3: Seminars in nanosimilars

As a very interesting novelty in this year’s programme, the 3rd-day agenda consisted of professional Seminar sessions dedicated to the nanodrug development topic with the participation of invited expert lecturers from the field of nanotechnology-formulated drug research.

In the morning session, Raj Bawa (Founding Director of American Society for Nanomedicine) delivered a 2-part seminar about the current perspectives in the era of biosimilars and nanosimilars. He gave a thorough overview of this topic, touching the current challenges in drug R&D in the fields of biologics, nanomedicine, bio- and nanosimilars, pointing out the technological as well as the market trends and business aspects, covering the topics of the evolving regulations, patenting and future development opportunities. Translational challenge in medicine at nanoscale has been presented, as well as the whole translation process including all steps from basic research toward drug registration. Basics related to biological products has been described, including but not limited to explanations of their complexity level along with numerous examples from practice. Finally, Dr. Bawa gave a detailed description on nanotechnology and a detailed overview for the fields of targeted nanomedicine, bio- and nanosimilar drug development. Specifically related to this topic – different material types, route of administration, as well as various factors influencing safety and efficiency of the nanodrugs were extensively discussed.

In the following session of the forum, Marina Dobrovolskaia (Head of the Immunology Section at the Nanotechnology Characterization Laboratory) showcased her online presentation about the immunological characterization of nanotechnology-formulated drugs and she gave deep insight into the achievements, disappointments and lessons learned over past decade from the developments in the area of this highly complex drugs. During the presentation Dr. Dobrovolskaia pointed out the importance of endotoxin screening for preventing erroneous data and corresponding wrong conclusions. Potential problems with immunogenicity of protein based APIs or targeting ligands due to the endotoxin presence were commented. Challenges related to the translation of therapeutic nucleic acids from bench to bedside were raised, including the importance of immune-mediated toxicities causing product development discontinuation. The importance of understanding mechanism of toxicity for the creation of safe and efficient complex drug systems was also discussed during this session.

The nanomedicine part of the event was further strengthened by Gert Storm, who presented an interesting overview about the current status and future opportunities in the use of nanoparticles for drug targeting. Opportunities to achieve increased therapeutic index through targeted nanomedicines able to favourably change the efficacy/safety balance were discussed. Prof Storm shared his experience related to major limitation of IV nanoparticulate drug targeting has been presented in dynamic and comprehensive way. Special attention has been draw on extravasation through ‘leaky’ vasculature – EPR effect which can, by improving accessibility, positively affect drug efficacy. The use of EPR passive drug targeting to tumor was also presented through practical examples.

In the final discussion section of the conference, the participants had a highly constructive conversation about the future perspectives of bio- and nanosimilars, recent developments, as well as regulatory challenges in the field of innovative drug development.

The audience of the Forum comprised various professions like regulators, medical scientists, clinical researchers, experienced biostatisticians and other representatives of the pharmaceutical developer companies. The size (around 100 participants in total) and the cozy atmosphere of this event enables not only rigorous methodological presentations but also sincere and friendly discussions as well as professional networking. All the participants agreed that – like the previous two forums hosted by Accelsiors – this was a very fruitful meeting, helping to share problems, to crystallize ideas, and it might contribute to the development of new guidelines and changing the old ones if needed.

5 – 6 OCTOBER, 2017 Budapest, Hungary

Account of experiences about the 2nd Annual Biosimilars Forum

World’s prominent biosimilar development experts have returned to Budapest to the 2nd Annual Biosimilars Forum on 5 – 6 October, 2017.

Accelsiors CRO has partnered with the Viennese Section of the International Biometric Society and the Hungarian Society for Clinical Biostatistics once again to deliver this unique professional forum for research management, leadership and support teams working in and for biosimilar drug development.

The professionally very fruitful 2nd Biosimilars Forum was hosted in Budapest, 5 – 6 October, 2017 by Accelsiors CRO with participation of internationally renowned experts of biosimilar drug development such as Prof. Dr. László Endrényi (Professor Emeritus of University of Toronto), Andrea Laslop (Head of Scientific Office, Austrian Medicines and Medical Devices Agency), Helmut Schütz (Owner at BEBAC – Consultancy Services), and clinical researchers, biostatisticians, regulatory professionals and sponsors from around the world.

This year’s two-day forum covered important issues and specific areas of debate facing clinical development teams specialized on biosimilars. The program of the event was very comprehensive and integrated multiple perspectives on current biosimilar research.

Focused on statistical and regulatory perspectives of biosimilar development

The 2nd Annual Biosimilars Forum welcomed László Endrényi Professor Emeritus from the University of Toronto who presented a lecture about Scientific factors in biosimilar product development. A very substantial course was delivered by Helmut Schütz, owner at BEBAC – Consultancy Services, who gave a detailed overview about open issues in the assessment of bioequivalence and biosimilarity.

The EMA regulatory expert Andrea Laslop showcased her keynote presentation about the 12 years of biosimilars in Europe and provided an essential understanding of the European regulatory framework. The regulatory part of the forum was further strengthened by Ina-Christine Rondak’s lecture (Seconded National Expert from Technische Universität München to EMA), she presented a useful overview of regulatory perspective on comparison of quality attributes in drug development.

As a very interesting novelty in this year’s program Prof. Janos Szebeni, Director of the Nanomedicine Research and Education Center delivered a keynote presentation about the immune side effects and unsolved issues in bio- and nanosimilar development.

The program of the event gave deep insight into the statistical perspective of biosimilar research. The prominent lecturers such as László Tóthfalusi (Associate Professor of Semmelweis Medical University), Bernd Jilma (Vice Chair, Department Clinical Pharmacology, Medical University of Vienna) and Johanna Mielke (Biostatistician at Novartis Pharma AG) provided an overview about scientific principles and methodologies used in the design and analysis of biosimilar studies as well as their recent industry experiences.

The members of the round table section from industry, regulatory and academic site had a really fruitful and constructive discussion both on actual challenges and open issues of biosimilar development. The participants of this open discussion such as Stephan Lehr (Biostatistician, Austrian Medicines and Medical Devices Agency and President of Viennese Section of IBS), Heike Wöhling (Head of Biostatistics, Sandoz Biopharmaceuticals), Ildikó ARADI (Head of Clinical Development of Biologics, Gedeon Richter Plc., Vice-Chair, European Generic medicines Association – European Biosimilars Group), Franz KÖNIG (Associate Professor at Medical Unversity of Vienna, Section for Medical Statistics), Vid STANULOVIC (Consultant, Clinical Development and Pharmacovigilance) had a highly constructive conversation about regulatory and industry perspectives of biosimilars, recent developments, as well as about essential statistical methods and high-level research.

The organizers are delighted that they could establish an opportunity with this event series for a constructive and open dialogue between medical statisticians, regulatory professionals, clinical researchers and sponsors with whom they collaborate and many interested people visited the event to learn and network. Visitors could take part in the experience with some of the world’s most prominent experts of this innovative field who gave a detailed overview in biosimilar product development and gave a guidance how to adjust clinical research practice to effective legislation or vice versa, raised ideas on how legislation could be developed further to meet the challenges this quickly developing field pose.

The organizers of the 2nd Annual Biosimilars Forum are proud that they once more had the chance to support biosimilar development professionals and they have assisted in sharing of recent scientific and practical knowledge aimed at increasing effectiveness of drug research.

OCTOBER, 2016 Budapest, Hungary

Account of experiences about the 1st Annual Biosimilars Forum

The very successful 1st Annual Biosimilars Forum was hosted in Budapest on October of the last year by Acclesiors CRO with participation of international scientific experts such as Shein-Chung Chow (Professor of Duke University School of Medicine), Prof Dr. László Endrényi (Professor Emeritus of University of Toronto), and clinicians, statisticians and regulatory representatives gathered together from around the world to share with each other their perspectives on this hot topic of research in lectures and informal discussions.

Shein-Chung Chow (Professor, Department of Biostatistics and Bioinformatics, Duke University School of Medicine; Special Government Employee and statistical consultant of the US FDA; Editor-in-Chief of three journals including the Journal of Biopharmaceutical Statistics, Drug Designing, and the Journal of Biosimilars), invited guest lecturer gave a thorough overview of the topic on the first day, touching the design and analysis of biosimilar studies, providing an overview of current FDA regulatory requirements for assessing biosimilarity of biosimilar products and giving a detailed description of the fundamental differences and assumptions between the chemical generic products and follow-on biologics. ”I think the development of biosimilars is heading for a great future” – he pointed out, illustrated by the increase in spending and sales in the industry and giving some insight into the history and current situation of submissions in the field. Johanna Mielke (Biostatistician, Novartis Pharma AG) provided a bigger picture through a systematic review of authorised biosimilars in the European Union. ”Biosimilars are essentially cheaper than the original drugs” – said Prof. Dr. László Endrényi (Professor Emeritus, University of Toronto; Former President of Canadian Society for Pharmaceutical Scientists), key lecturer of the event, thus it is not only a business opportunity for developers to put them on the market, they also foster having sustainable health care systems and are ultimately of the interest of patients.

However, as biosimilars emerge as a rapidly growing segment, there are challenges to overcome and questions to answer. Challenges begin with manufacturing: as compared to small-molecule generic products, in the case of biosimilars ”it is much more difficult to imitate the original product” – continues Prof. Dr. László Endrényi, which in fact has an effect on sale prices: ”Whereas a generic product can be 50-70% cheaper than the brand name drug, in the case of biosimilars the difference would be perhaps 20-30%. But that is still a lot, because biological drugs are very-very expensive”. The speciality of manufacturing biosimilars is also reflected in the fact that „right now there is a major concern that the EU and US licenced reference products are not really similar in some cases”, adds Shein-Chung Chow, which can undermine intentions to prove biosimilarity of a drug simultaneously to both references.

This latter issue raises the question of harmonization between regulatory requirements of the EMA, FDA and beyond, however it appears that there is room to improve on currently existing non-global legislation as well. Commenting on the currently existing EMA guidelines, Ildikó Aradi, Head of Clinical Development of Biologics at Gedeon Richter Plc. noted that ”the European Agency has a pioneering role in biosimilar development and they are taking some next steps”, as several further guidances are under development, further commenting that „the guidances that we have now are good and they are flexible”. This implies that „there is still some lack in some areas where there could be more guidance”, as Stephan Lehr (Biostatistician, Austrian Medicines and Medical Devices Agency) adds. Prof. Dr. László Endrényi had some concerns regarding the United States legislation and beginned with a comparison: „ The pathways are very-very different in the European Union and the United States. In Europe they go almost product by product and there are some guidelines for each product class. In the United States they try to have a big encompassing legislation which covers everything – and it cannot.” In his lecture, he pointed out that having limited authority, central regulators (EMA and US) do not always take responsibility over issues, such is the case with interchangeability which leads to de-centralised solutions. There was a consensus amongst participants of the event that globally harmonized guidelines would be desirable and events attaining international attention like this are bringing us closer to achieving it.

Stephan Lehr touched in his presentation methodological issues discussed with authorities in the planning stage and gave some insights into assessment from a regulatory point of view. Andrea Laslop (Unit Head, Austrian Medicines and Medical Devices Agency) gave a presentation about the concept of ’totality of evidence’ adjusted for biosimilars, and discussed how to avoid pitfalls in the step-wise approach at the quality, non-clinical and clinical levels to develop evidence of biosimilarity. Establishing biosimilarity on the quality attributes level was further discussed by Martin Wolfsegger (Associate Director, Shire). Vid Stanulovic (Consultant, Clinical Development and Pharmacovigilance) discussed in his presentation which specialties of biosimilars have to be considered when it comes to demonstrating similarity of clinical safety.

The forum provided the opportunity for lecturers to share their own concepts with the audience, including Shein-Chung Chow, who recognised that approaches used for generics are not entirely appropriate in case of biosimilars: he presented his proposed criteria for biosimilarity and a biosimilarity index developed by him and collegues. László Endrényi presented a proposal for a new criterion for interchangeability (SCDI), similar to the scaled average bioequivalence (SABE) approach. Júlia Singer (Chief Scientific Officer, Accelsiors Ltd) went into highlighting that the application of imputation methods has to be aligned with the purpose of a trial and as such specific considerations have to be taken into account in case of biosimilars.

Having a successful and professionally fruitful event, at its end the organizers expressed their intention to continue the series next year, as Júlia Singer concluded on behalf of organizers: ”it fits into our past, presence and future as well”.