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Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
Innovations in-biosimilar-product-development
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Innovations in-biosimilar-product-development

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Innovations in-biosimilar-product-development

Innovations in-biosimilar-product-development

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  • 1. www.healthnetworkcommunications.com/biosimsus Thoughts from top industry opinion leaders eBook Contributors Dr Alex Kudrin, Medical Assessor in Licensing of Biological Products, MHRA Rajiv Dua, Analytical and Stability Coordinator, Lupin Biotech Roman Ivanov, Ph.D, Vice President, Research & Development, CJSC BIOCAD Jim Roach, M.D., FACP, FCCP, Senior Vice President, Development and Chief Medical Officer, Momenta Pharmaceuticals, Inc. Anjan Selz, CEO, Finox
  • 2. The potential benefits that biosimilars offer are well celebrated through providing improved patient access to affordable, effective and complex treatments. The demand for affordable treatments in the face of escalating healthcare costs is high but a number of hurdles present themselves when bringing a biosimilar from bench to market. In this rapidly changing marketplace with its recently implemented and still evolving regulatory framework, it is critical to adopt the right strategy, overcome barriers to entry and stay ahead of the game. The starting point is to have a solid understanding of biosimilar development and the clinical trials environment. We asked some industry and regulatory experts to provide their opinion on best practice in biosimilar development, manufacturing and clinical stages. Take a look at what they had to say. Alice Fairchild General Manager Biosimilar Drug Development World Americas +44 (0)207 608 7054 afairchild@healthnetworkcommunications.com www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................
  • 3. Dr Alex Kudrin Medical Assessor in Licensing of Biological Products MHRA What are the current hurdles that you face in biosimilar development? There are numerous regulatory, development and legal resistors to development of complex biosimilars. Some of the challenges could be divided into two groups: internal factors related to lack of expertise in developing biosimilars and external challenges related to stakeholders and competitive forces that are driven by reference product developers. The problem is that many biosimilar companies as well as some regulatory agencies are still learning from the "first time experiences and trial and error approach" with complex biosimilars. Second group of factors represent external factors attributed to regulatory barriers in some regions (even in the US despite that new guidelines were recently enacted by FDA), clinical environment hurdles associated with the lack of education amongst prescribers and support from some key opinion leaders. These hurdles are often triggered by the fact that prescribers are relatively familiar with the use of reference products and unfamiliar with the concept of biosimilarity. Lets not forget the fact that some key opinion leaders also were providing input in development and clinical trials with reference products and therefore might be biased towards competitive biosimilar development. Increasingly a new wave of biosimilar-driven key opinion leaders is emerging in developing markets. Inherently, some prescribers are concerned about theoretical risks associated with switching between reference and biosimilar products. Despite of the contrast between EU and US regulatory positions on the interchangeability requirements, most of biosimilar developers will have to address the interchangeability issue at some stage in the life cycle of the product as this might be a critical factor in determining a market size. Biosimilar developers will need to drive a global educational campaign on the use of both biologics and biosimilars especially in emerging markets where the use of biologics was, until recently, relatively uncommon. What are the hurdles in qualifying biosimilarity between a reference product and comparator? Not many companies are capable to successfully complete a first step of quality and in vitro functional comparability. Unfortunately a stepwise approach is not always followed and some developers launch clinical studies well before initial steps of biosimilarity exercises are fully concluded. In vitro functional assays represent a pivotal step in demonstrating biosimilarity and not many developers either develop a full armamentarium of functional assays and cellular assays or do not fine-tune results of these assays with non-clinical and clinical steps of development. Therefore some differences in the performance of antibodydependent functions may preclude these products from being qualified as biosimilars or indeed preclude the extrapolation of all available clinical indications. There is also a great deal of confusion in industry around so called "biobetters" which are nothing to do with appropriately defined biosimilar products. Hence some developers consider using different primary sequence structures or heterogeneous expression systems in developing biosimilars. Because "biobetters" potentially may exhibit dramatically different features to those known with reference products, such as enhanced efficacy, different pharmacokinetic properties, different posology or route of administration, these products would not fall under biosimilar category and would have to follow “stand-alone” pathway for regulatory approval. Cont... www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................
  • 4. Hence inappropriate use of “biosimilar” term around products that would be normally classified as “new biological substances” can be damaging to nascent biosimilar industry striving to develop high-quality and highly similar products. Do you feel the clinical trial environment for biosimilars is robust? There are numerous challenges in clinical trial environment for biosimilars. Firstly, there are ethical issues around appropriate consenting of patients who participate in biosimilar studies, especially if those enrol healthy volunteer subjects. The assay sensitivity in pharmacokinetic and therapeutic equivalence studies should be robust enough to identify any potential differences between the reference and biosimilar. This possible to achieve in most sensitive settings and less heterogeneous patient population. As a consequence, biosimilar studies are invariably carried out in patients who are naive to reference products and in order to identify sufficient number of patients companies are forced to open numerous clinical sites across the globe, primarily in developing countries. There are particular hurdles in conducting oncology biosimilar studies. The rate of patient recruitment can be very slow due to low number of available patients and growing competition between numerous biosimilar developers for conducting studies at the same sites. Therefore the future regulatory requirements around the size and scope of required oncology studies should be revised in accordance with evolving clinical trial environment and accumulating experience with approved biosimilar products. An overarching biosimilar guideline by the EMA is currently under revision and, as the concept paper details, the position on different study design might be further finetuned in the new draft. There might be scenarios where due to the heterogeneity of the clinical condition and the highly variable performance of clinical outcomes, the conduct of equivalence studies will not be feasible. These scenarios include evaluation of overall response rates and disease free or overall survival in oncology indications or assessment of multiple sclerosis activity ( e.g. for biosimilar natalizumab or interferons). In some of these complex cases, the PK-based equivalence may not be straightforward as PK/PD relationships with disease activity are not very clearly defined. Therefore, in some cases, supportive noninferiority studies might be allowed in the future along with PK equivalence approach, or PK equivalence study alone might be sufficient to complete a clinical biosimilarity exercise. In addition, sensitive but not necessarily approved indications might be allowed for comparability exercise. However there is no harmonised regulatory position on this matter yet. Therefore in order to comply with EU, US and other regulatory requirements, developers may need to address the requirements imposed by different agencies in one single (but relatively complex) or in several biosimilar studies. The situation will be much more harmonised and clearer as soon as first complex biosimilar monoclonal antibodies will be approved both in the EU and USA. www.healthnetworkcommunications.com/biosimsus www.healthnetworkcommunications.com/biosims ............................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................
  • 5. Roman Ivanov, Ph.D. Vice President, Research & Development CJSC BIOCAD What are the current hurdles that you face in biosimilar development? Uncertainties in regulations regarding biosimilars on many emerging markets represent a major obstacle for biosimilar developers. These uncertainties in combination with lack of proper expertise of regulators create an environment where commercial success is not always guaranteed for those companies that use science-based approaches for biosimilar development. In addition, originators put a lot of effort into creating a negative attitude towards biosimilars among prescribers and regulators, decreasing market penetration of biosimilars. What are the hurdles in qualifying biosimilarity between a reference product and comparator? Procurement of multiple batches of innovator’s product from different target markets sometimes requires significant time and resources. However, it is necessary for justification of an acceptable margin in comparability studies. Do you feel the clinical trial environment for biosimilars is robust? Conducting a clinical trial for biosimilar product in a situation when multiple companies (both biosimilar developers and innovators) are performing clinical trials in identical patient population is a real challenge. What is your organizations approach to biosimilar development? BIOCAD approach is to perform analytical characterization and nonclinical studies in accordance with EMA guidelines, while clinical development strategy is adapted to expectations of regulators from our target markets. www.healthnetworkcommunications.com/biosimsus www.healthnetworkcommunications.com/biosims ............................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................
  • 6. Rajiv Dua Analytical and Stability Coordinator Lupin Biotech What are the current hurdles that you face in biosimilar development? I think for Biosimilar development today, the major hurdle is less clarity and complexity in terms of intellectual property and lack of marketing strategies besides huge cost involved in complicated manufacturing, establishing physicochemical and Clinical comparability to get the biosimilar products comparable to Reference Medicinal Product (RMP) in terms of quality, Safety and Efficacy. Analytical characterization incapability is other technical hurdle. What are the hurdles in qualifying biosimilarity between a reference product and comparator? Unlike traditional generic pharmaceuticals, biosimilars aim to copy a complex recombinant, three dimensional protein structures with high molecular weight. Small changes in the manufacturing process can alter the product’s effect and safety. The first challenge in assessing the comparability of biologics is understanding exactly what is meant by the terms ‘comparable’, ‘similar’ and ‘highly similar’. Despite such significant improvements in analytical techniques, however, current analytical methodology are not be able to detect all relevant structural and functional differences between two proteins, that’s the reason extensive animal and clinical studies are need to determine comparability (These factors increase the time and money investment). is required after post approval. What is your organizations approach to biosimilar development? While conventional generics are expected to face competition and pricing pressures in most developed markets, Lupin pharmaceutical have already started gearing up for biosimilars. Lupin LTD (Biotech Div.) have outlined plans, identified products and set aside investment budgets to develop a robust product pipeline. Lupin is now on its way and plans to soon launch its first of two biosimilar drugs for oncology in India by the end of this year. The company currently has a total of 10 proteins in different stages of development. www.healthnetworkcommunications.com/biosimsus www.healthnetworkcommunications.com/biosims ............................................................................................................................................................................................................................................... Do you feel the clinical trial environment for biosimilars is robust? Due to the limited clinical database at the time of approval of a biosimilar, vigorous pharmacovigilance ...............................................................................................................................................................................................................................................
  • 7. Jim Roach, M.D., FACP, FCCP, Senior Vice President, Development and Chief Medical Officer, Momenta Pharmaceuticals, Inc What is Momenta’s approach to biosimilar development? Momenta’s approach to biosimilar development is very much in line with the approach outlined in the three FDA draft guidance documents on biosimilar development (see further below). We begin by structurally and functionally characterizing a reference protein product (RPP) as deeply as is technically feasible. Our goal is to determine “fingerprints”, or very specific molecular product attributes and patterns that fully define the RPP. Our analytics and scientific approach have facilitated the development of generic versions of complex drugs such as enoxaparin (approved in the US in July 2010) and glatiramer acetate (currently under FDA review), and it is this prior experience that has given us an appreciation on how product quality attributes (PQAs) for biologic products may be controlled and modified from clonal selection through downstream process development. We believe that determining relevant RPP “fingerprints”, combined with our understanding of PQA controls, will allow us to reverse engineer the process in order to develop not only biosimilar, but also potentially interchangeable biologic products. Following extensive characterization of the RPP, we then compare it to our product and evaluate the extent of similarity/equivalence. In the event “residual uncertainties” remain, these will be evaluated for potential clinical significance and addressed by additional studies as needed. Our hope and expectation is that to the extent we have been able to thoroughly understand the RPP through this extensive “fingerprint-like” characterization, the scope of any clinical studies required, if any, may be substantially reduced relative to competitors in this space. We have as a goal the development of technology that will enable, over time, the ability to reduce “residual uncertainties” to not only minimize, but potentially eliminate clinical trials for some products. We also believe that thorough structural and functional characterization may offer viable means for demonstrating, in whole or in part, “interchangeability” and reducing any “residual uncertainty” associated with that decision. What are the key takeaways from the FDA draft guidance? Key takeaways from our perspective across the three guidance documents include, but are not limited to: The Agency “encourages the Sponsor to initiate early discussions” and frequent consultation. The Agency will use a “stepwise,” “risk-based,” “totality of the evidence” approach to evaluate biosimilar candidates, allowing for the science to dictate additional requirements (if any) following review of structural and functional characterization data. There is a certain degree of flexibility to facilitate development, with FDA retaining scientific discretion to review each application on a “case-bycase” basis without a priori mandating requirements; noting that the “assessment of one element at one step can influence decisions about the type and amount of subsequent data for the next step.” The FDA supports “fingerprint‐like” characterization using multiple complementary analytical methods with high sensitivity. Data derived from analytical studies, animal studies, and a clinical study/studies will be required for biosimilarity unless FDA determines an element unnecessary. What are the scientific studies needed to establish and qualify the similarities and differences between a protein reference product and comparator? Without providing an exhaustive list of specific analytics/tools (e.g., mass spectrometry, certain in vitro or in vivo assays, etc.) or endpoints, in general, the scientific studies needed for comparator development should include whatever technology and assays that will provide a comprehensive picture of the structure and function of, and process-related fingerprints associated with, both the RPP and comparator product. At Momenta, we use multiple, redundant, and orthogonal assays to permit a thorough understanding of both products. We believe that this approach is the most appropriate and efficient way to demonstrate to extent possible “structural and functional equivalence” and assure that the patient experience with the comparator product will be the same as with the RPP. www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... . ...............................................................................................................................................................................................................................................
  • 8. www.healthnetworkcommunications.com/biosimilaramericas www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... Anjan Selz, CEO, Finox What are the current hurdles in biosimilar development? The major issue we are confronted with at FINOX Biotech is the nonhomogenuous regulatory landscape across the globe. And this makes biosimilar development a very tough venture. Even-though the development pathway may be somewhat abbreviated compared to a new biologics development, still and in general, you have to present a very comprehensive data set in order to obtain approval. Such comprehensive data set results only by conducting extensive process, product and patient studies, head-tohead to your reference product and that take years to conclude and absorb millions of dollars. And for the sake of patient safety, this is definitely ok. But, given that biosimilars do not cover an unmet need and are competing from day one on in a mostly saturated market, such heavy development costs do not results in attractive business cases for all biosimilar candidates. If such development costs are then further multiplied due to non-homogenuous expectations by regulatory agencies across the globe, then even less bioismilar candidates will make up a good business case. And given that situation, how should the industry then cope with the healthcare payor's expectation to have more affordable drugs brought to the patient? What are and how do you assess the IP challenges? The most challenging issue in IP is how to assess freedom-to-operate (FTO) for one's product and processes. The loss of patent protection for the molecule and its expression system is a good beginning for FTO, but probably not the area where patent issues will be fought over. Given the numerous production and analytics processes involved for manufacturing a biologic and also given that such processes may be applicable to products totally different to the one you are assessing, it is extremely difficult to obtain a clear YES from the patent attorneys in regards to FTO. Further areas of uncertainty are composition of formulations, use of excipients and other elements involved in producing and presenting a final product. And finally, there are even some legislations that know patents of use that would theoretically block the use of a given competitor product. On top of this comes the complexity of the IP landscape not being a static but a dynamic issue. And be it competing biosimilar developers, or be it originator companies defending their market share, there will be certainly someone who tries to block your market entry by issuing new patent applications and claims along your product and process development - and it may be difficult to avoid these the further your development has already advanced. ...............................................................................................................................................................................................................................................
  • 9. Join the conversation Click here to leave a comment about this ebook on the Total Biopharma blog Click here to contribute to our LinkedIn discussion Click here to follow us on Twitter @healthnetwork Click here to sign up for the Total Biopharma e-newsletter www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................
  • 10. We’re hosting Biosimilar Drug Development World 2013 in Boston this November 19-21 and would love to see you there. Biosimilar manufactures will be discussing: •Overcoming the challenges in development and commercialisation •Regulatory issues surrounding biosimilar development •Manufacture, process development and scale up •Immunogenicity testing required •Best practices in clinical trial design and execution •Sourcing innovators for all levels of research www.healthnetworkcommunications.com/biosimsus ............................................................................................................................................................................................................................................... & much more! It’s a business event Biosimilar Drug Development World America will discuss the scientific and technical considerations needed to navigate the challenges in manufacture and development of biosimilar medicines. The sessions will include case studies, discussion and insight about the application on biosimilar manufacture and development. This year’s event features Hospira, Pfizer, Baxter, Polpharma, Momaneta Pharmaceuticals, Rothschild, Novartis, Sandoz, & many more. Learn from them to manage the complexities in biosimilar development. www.healthnetworkcommunications.com/biosimsus ...............................................................................................................................................................................................................................................

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