The case for biosimilar monoclonal antibodies: Ask the experts - biosimilar speaker tour

Transcription

1 The introduction of biosimilars to the New Zealand health system The case for biosimilar monoclonal antibodies: Ask the experts - biosimilar speaker tour July 2012

2 1 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 2 In July 2012, Roche hosted two leading experts in the field of biological medicines to speak with MedSafe, PHARMAC and New Zealand healthcare professionals. The objective of the meetings was to ensure the ongoing safe and responsible introduction of biosimilars to the New Zealand health system. Executive summary The safe and responsible introduction of biosimilar monoclonal antibodies to the New Zealand health system has the potential to widen access to biologic treatments for many patients suffering from cancer and chronic inflammatory diseases. Phase III clinical studies together with ongoing pharmacovigilance are essential to understand the immunogenic potential of all monoclonal antibodies innovator and biosimilar. 1,2 The European Medicines Agency (EMA) recognises the added complexity and safety issues associated with monoclonal antibodies and has published specific monoclonal antibody biosimilar guidelines outlining expected standards. 1 Adopting the EMA monoclonal antibody biosimilar guidelines provides an opportunity for New Zealand to apply rigorous standards of reviewing clinical data and ensuring patient safety. Extrapolation of indications will require clear and robust scientific justification, particularly where the mode of action is poorly understood. 1 Monoclonal antibody biosimilars: Considerations when assessing biosimilarity Is the product already approved by a major regulatory authority? (e.g. EMA, FDA, or TGA) What clinical data has been provided to support the registration? (e.g. Study design and size, indications, length of follow-up) What safety data is known to support the proposed indications? Has immunogenicity been studied in each proposed indication? Were sensitive populations used for the clinical trial programme? Does the product have a unique name? Has the sponsor established a programme for pharmacovigilance? Does the registered indication support the proposed funding criteria? Introduction Dr Thomas Schreitmüeller focused on the scientific, technical and regulatory aspects of biosimilars 3,4 while Dr Frank Scappaticci spoke about the clinical challenges with biosimilar drug development. 4,5 Particular attention was paid to monoclonal antibodies and the increased complexity faced by both manufacturers and regulators in attaining and assessing an acceptable level of similarity to an innovator product. 3-5 The timing of the presentations was especially relevant given the first monoclonal antibodies attempting to achieve biosimilar status were completing Phase III clinical trials with intended copies of products such as infliximab, rituximab and trastuzumab getting closer to filing for regulatory approval. In anticipation, the EMA has published specific regulatory guidelines to address the increased complexity of monoclonal antibodies. 1 Together with many other non-european countries, New Zealand medicines regulator MedSafe has indicated support for EMA biosimilar guidelines. 6 In New Zealand MedSafe has already approved three of the less complex biosimilars including one erythropoietin (EPO) and two granulocyte colony-stimulating factor (G-CSF) products. 7 In addition, one of these, a biosimilar filgrastim, has been granted funding by PHARMAC. 8 All eyes will be on Europe in the coming months where it is anticipated the first of the complex monoclonal antibody biosimilar applications will come under intense scientific and regulatory scrutiny. Achieving EMA approval is likely to signal an advance preview of biosimilar monoclonal antibodies that may seek registration and funding status in New Zealand. Roche New Zealand believes it is important for all stakeholders to understand the critical issues in advance of biosimilar monoclonal antibodies entering the New Zealand health system. This supplement reviews the key issues and aims to provide a platform for further discussion on how both patients and the health system can benefit from widened access to monoclonal antibody products whilst preserving patient safety, clinical efficacy and medicine quality.

3 3 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 4 Biosimilar regulations rationales and requirements 3,4 Complexity of the process and the product Dr Schreitmüeller opened the Auckland healthcare professional briefing by asking the audience why the term biosimilar rather than bio-generic is used to describe an approved copy of a biologic medicine? The answer lies in the complexity of the living cell that is the starting material, combined with the highly complex manufacturing processes undertaken on the cell to create the final product. Unlike small molecule or chemical medicines, this makes producing an exact copy - or generic - of a biologic medicine impossible. 4 Instead, biosimilar is the name given to a copy of an innovator biologic product, that has been proven through preclinical and clinical trials to have sufficient similarity to the innovator to be approved for use. 9 If you synthesise a small molecule you have to control approximately 4,000 process parameters. If you make a biotech product you have to control 60,000 process parameters. 4 Dr Schreitmüeller summarised the complex manufacturing process by saying each manufacturing stage confers unique properties to the resulting biological protein mixture. Only a deep understanding, extensive process validation, and a unique control strategy will ensure the consistency of a biological product produced by an established process. 3,4 Immunogenicity Dr Thomas Schreitmüeller holds a Diploma and PhD in Biochemistry from the University of Munich (Max Planck Institute for Biochemistry, Munich, Martinsried and Institute for Clinical Chemistry and Clinical Biochemistry University of Munich). In 1989 he joined Roche holding various positions in the biotech area. Since 2003 Thomas has been the head of Analytical R&D and Quality Control Biotech Products at Roche in Basel, Switzerland. The department assumes responsibility for basic analytical research of biotech products and is responsible for the quality control of Roche marketed products. In 2010 Thomas became the global lead for technical regulatory policy and strategy for biologics within Roche. The complexity of biotherapeutics innovator and copies - was further emphasised by Dr Schreitmüeller in a segment dedicated to safety. Immunogenicity is the safety issue associated with biotech products. You will not see anti-product antibodies form against synthetic molecules. 3,4 Immunogenicity is the production of host antibodies directed against a therapeutic molecule. It can vary from being mild with no clinical consequences through to being very serious and potentially life-threatening. 9,10 The potential consequences of clinical immunogenicity include safety and efficacy aspects. Specific safety concerns include hypersensitivity reactions, receptor signalling related to cross-linking and the neutralisation of the endogenous counterpart. For example, if I inject an interferon and my immune system develops antibodies against this interferon it also may neutralise the interferon my own body is producing under normal circumstances. This could have dramatic consequences for the patient. 3,4 With respect to efficacy, the immune response has several potential clinical outcomes including neutralising the effect of the therapeutic protein, modulating the pharmacokinetic profile, or potentially even changing the bio-distribution. 3,4 Factors that influence a biotherapeutics potential to induce an immune response can be divided into product specific factors such as impurities or structural changes and patient specific factors such as genetics, disease state or immune competency. 3,11 Figure 1: Factors that potentially trigger an immune response 3 Product specific Structural Aggregation Degradation Oxidation/Deamination Glycosylation Impurities Application specific factors Route of delivery (IV, IM, SC) Dose and frequency of administration Dr Schreitmüeller explained how patient specific factors such as immune competency could potentially trigger an immune response. If a patient is treated with chemotherapy and you inject a human protein it is highly unlikely that you will see an immune response. This is because the immune system of this patient is highly compromised by the chemotherapy applied in parallel. But if you injected the same protein into a patient who is not receiving chemotherapy, they may develop an immune response. This is why we always have to investigate immunogenicity in different patient populations. 3,4 Immunogenicity: Issues specific to monoclonal antibodies Dr Schreitmüeller went on to discuss monoclonal antibodies in particular. Antibodies are more complex than the smaller EPO s or G-CSF molecules. 3 As the use of monoclonal antibodies increases around the world, characteristics of their safety profile become apparent, including immunogenicity. 12 Almost all recombinant proteins develop an immune response in the patient. The specific issue with monoclonal antibodies is the risk of human anti-drug antibodies (HADAs) forming in patients. 12 Anti-antibodies can be further differentiated according to their target at the therapeutic mab (monoclonal antibody) (figure 2). 12 Dr Schreitmüeller elaborated: The functionality is not only in the binding region, but also in the constant region of the antibody. For example all of the factors involved in cell killing are located in the constant region. When antibodies are formed they may neutralise the target binding but they may also neutralise these effector functions that are involved in cell killing. 3,4 Figure 2: Anti-antibodies differentiated by target site, exemplified by a classical mab and an antibody fusion protein. CDR: complementary determining region; Fc: Fragment crystallisable, constant antibody part. anti-antibodies against Fc region anti-antibodies against CDRs Patient specific Immune competency Pre-existing antibodies Disease state Genetics Age Gender Target biology Cell-bound vs. soluble target Target on immune cell surface anti-antibodies against light chain anti-antibodies against Fc region anti-antibodies against fusion domain Adapted from Niebecker and Kloft 12

4 5 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 6 Dr Schreitmüeller emphasised that immunogenicity responses can vary significantly even when considering a single biologic product. Table 1 summarises the immunogenicity of monoclonal antibody adalimumab across several chronic inflammatory disease indications. 12 In each and every indication you have different immunogenicity in each and every population. What you also see is that the immunogenicity varies drastically if the patient receives methotrexate or if they don t receive methotrexate. These findings highlight the importance of studying immunogenicity in all relevant populations. 3,4 Table 1: Immunogenicity of adalimumab 12 Indication Rheumatoid arthritis PJIA Psoriatic arthritis Ankylosing spondylitis Crohn s disease 2.6% Psoriasis 8.4% Frequency [Overall, w, w/o Co-Medication] 5.5%, 0.6% w. 12.4% w/o MTX 15.8%, 5.9% w. 25.6% w/o MTX 10.1%, 7.1% w. 13.5% w/o MTX 8.3%, 5.3% w. 8.6% w/o MTX Consequences: Pharmacokinetics Efficacy Safety Clearance Efficacy No apparent effect Based on information from the European Public Assessment Reports. Adapted from Niebecker and Kloft 12 MTX: methotrexate; PJIA: polyarticular juvenile idiopathic arthritis; w, w/o: with, without. Biological products Summary: In contrast to uniform small molecule products, biological products are complex, sensitive and heterogeneous mixtures of protein molecules. Any change in the composition of the product mixture can affect patient safety and the chance of cure. 3,4 Dr Thomas SCHREITMüeller Regulating biosimilars: Generics process scientifically inappropriate The increased risk of immunogenicity combined with the inability to reproduce exact copies of biotherapeutics has led medicines regulators around the world to recognise the need for specific biosimilar guidelines. Both the World Health Organization (WHO) and the EMA have rejected the current generics approval process as scientifically inappropriate to handle the complexities of biosimilars. Consequently both organisations have issued specific guidelines for the approval of biosimilars. 10,13 The EMA guidelines have provided the regulatory framework necessary to ensure the responsible introduction of biosimilars in EU member states. Europe currently leads the world in widening patient access to proven biosimilars with 13 approvals across three product classes to date. 14 The EMA were the regulators driving the whole biosimilar concept on a global basis. 3,4 Dr Thomas SCHREITMüeller In June 2012 the EMA published the first guidance specifically targeted at biosimilar products containing monoclonal antibodies. 1 In addition, a second guideline addressing the immunogenicity assessment of monoclonal antibodies was published. 2 Both are due to come into effect in December In these documents the EMA is recognising the complexity of these compounds and that there are a number of poorly understood factors making it difficult to predict with any certainty whether a monoclonal antibody is likely to provoke a clinically relevant immune response. The EMA is therefore requesting a risk identification and assessment strategy from the manufacturers of monoclonal antibodies where the standard immunogenicity testing programme may be reduced with thorough justification, or may need to be intensified, depending on the level of risk. 4 Clinical challenges for establishing biosimilarity for monoclonal antibodies 4,5 Dr Scappaticci provided an overview of the clinical trial design considerations for biosimilars and how biosimilar studies are being done. He discussed issues around endpoints for biosimilar studies in a curative setting and if extrapolation of data across indications is feasible. Biosimilar versus innovator clinical studies: Issues for oncology Table 2 summarises how biosimilar clinical studies differ from innovator studies. Typically, the innovator does a superiority clinical trial design to prove it is better than the standard of care. A biosimilar does not have to establish benefit/risk as the innovator has already achieved this. What they need to show is equivalence to the innovator and this is done using a sensitive endpoint. These sensitive endpoints are not the traditional endpoints that the innovators have used such as progression free survival (PFS) and overall survival (OS). Instead, the biosimilar endpoints are usually the response rate. It s done that way because progression free survival; overall survival, would require thousands of patients and many years of development and no regulator is going to require that. Additionally the biosimilar has to show similarity around safety and immunogenicity. Guidelines indicate there could be a possibility for assumed clinical efficacy in other indications (extrapolation) with sufficient evidence. In comparison extrapolation is not something that is allowed for any innovator. 4,5 Table 2. Biosimilar versus innovator clinical studies in oncology: Differences on requirement and study design 5 Aspects of development Biosimilar Innovator Patient population Sensitive & homogenous (patients are models) Any Clinical design Comparative versus innovator, normally equivalence Superiority vs standard of care (SoC*) Study endpoints Sensitive Clinically validated PD markers Clinical outcomes data or accepted/ established surrogates (e.g. OS and PFS) Safety Similar safety profile to innovator Acceptable risk/benefit profile vs SoC* Immunogenicity Similar immunogenicity profile to innovator Acceptable risk/benefit profile vs SoC* Extrapolation Possible if justified Not allowed *In some cases standard of care may not exist Frank A. Scappaticci, MD, PhD is a clinical oncologist and haematologist working at Genentech/Roche. Dr Scappaticci obtained his undergraduate degree at Yale University in biochemistry. Subsequently, he trained at the University at Buffalo/Roswell Park where he obtained his medical and graduate degrees. He completed his internship and residency in Internal Medicine at the University of Pennsylvania. Following this, he obtained his Medical Oncology and Haematology training at Stanford University Medical Center. After a short period on faculty at Stanford and the University of California/Davis, he joined Genentech approximately nine years ago and has been working on late stage clinical trial development for bevacizumab. He has led numerous filings for bevacizumab that eventually led to approval for bevacizumab in colorectal, non-small cell lung, and renal cancers. Recently, Dr Scappaticci was appointed as the clinical science leader on the Roche Biologics Task force.

5 7 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 8 Curative versus metastatic cancer settings: Impact on biosimilar study design Dr Scappaticci went on to discuss managing residual uncertainty and risk when the outcome of treatment is cure. The metastatic cancer setting and the adjuvant cancer settings are different and perhaps the clinical designs of biosimilar studies should consider those differences. 4 For example, clinical data demonstrating recurrence free survival in an adjuvant or curative setting will have a long-term impact on reducing the number of patients entering the metastatic setting and consequently the expected mortality for the same period. Some biosimilar companies may want to extrapolate data from the metastatic setting to the early adjuvant setting without first conducting clinical equivalence trials. Is this a high risk? Because these patients are being cured, would we want to see additional clinical data in this setting? This is something to consider in terms of what additional work may be required. Perhaps stricter equivalence margins are needed? It might be difficult to justify extrapolation. These are the issues that need to be considered. 4 The importance of valid study endpoints for biosimilar studies An understanding of how the clinical response or efficacy of a medicine is measured is critical when designing trial programmes and confirming the validity of the endpoints chosen. Dr Scappaticci explained that it is especially important in the biosimilar setting as clinically meaningful pharmacodynamic endpoints do not yet exist in cancer. 4 In contrast, relatively simple biosimilars are often developed with clinically meaningful and robust pharmacodynamic endpoints as a valid measure of comparative efficacy with the reference biologic. Biosimilar filgrastim, for example, utilises neutrophil count whilst a biosimilar erythropoietin may utilise a combination of haemoglobin, red blood cell, haematocrit and reticulocyte counts to establish similarity. 4 Dr Scappaticci discussed the requirements set out in the new EMA guidelines for biosimilar monoclonal antibody study endpoints. What the Europeans have said around the clinical work that needs to be done is that pharmacokinetics and pharmacodynamics may not be enough when we talk about oncology. They may be for G-CSF and EPO where you can follow the neutrophil count or the red blood cell count where the pharmacodynamic marker is actually relevant. In oncology these [pharmacodynamic markers] don t exist. They just haven t been discovered yet that are clinically meaningful so keep in mind the differences in oncology versus these other areas where we have a pharmacodynamic endpoint available. In addition, safety experience has to be gathered. 4 Efficacy trials will need to be done in oncology and there is no way around that. 4,5 Dr Scappaticci rejected that B cell depletion with rituximab could be considered a pharmacodynamic endpoint as it is not a clinically meaningful pharmacodynamic endpoint. You can t use this endpoint of depleting B cells as your primary endpoint in a biosimilar study because it s not a validated endpoint for clinical outcome. 4,5 EMA: Clinical trials are required for monoclonal antibody biosimilars With particular reference to biosimilar monoclonal antibodies, the EMA have stated that if dose comparative and highly sensitive pharmacodynamic studies cannot be performed convincingly showing comparability in a clinically relevant manner, similar clinical efficacy between the biosimilar and the reference product should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blinded and normally equivalence trials. 1 Dr Scappaticci explains that the EMA biosimilar monoclonal antibody guidelines require the biosimilar efficacy studies to be undertaken in a homogeneous population using sensitive endpoints. These are normally equivalence trials and not necessarily non-inferiority trials. What s being said around this is that equivalence is the most important design because if a product is shown to be superior it could pass a non-inferiority trial but that product may not be biosimilar it may be a superior product. It may have a different mode of action; it may have a different safety profile. That s why equivalence trials are the preferred clinical design. 4,5 EMA: Sensitive human models required for monoclonal antibody biosimilars The new EMA guidelines for biosimilar monoclonal antibodies state that biosimilarity should be demonstrated in scientifically appropriate sensitive human models and study conditions (whether licensed or not), and the applicant should justify that the model is relevant and sensitive to demonstrate comparability in relation to efficacy and safety in the indication(s) applied for. 1 Dr Scappaticci explains that the idea is to study the biosimilar in the population of patients in whom if there is a difference between biosimilar and reference product that difference will be most easily detected. If we knew the patients that would respond to an agent, then those are the patients that should be chosen for the pivotal [biosimilar] study because that s the population that could potentially detect a difference between an innovator and a biosimilar instead of the all-comer population that might quench any difference. So if we knew those patients then those are the patients that make up the sensitive population. 4,5 The EMA requirement for biosimilar manufacturers of monoclonal antibodies to use sensitive patient populations was further explored by Dr Scappaticci using the example of trastuzumab in the adjuvant breast cancer setting versus the metastatic setting. Adjuvant may actually be the most sensitive for many different reasons. 4,5 For example, patients in the adjuvant setting may have less tumour burden after surgery - that could make it a cleaner population to study pharmacokinetics. It could make it a cleaner population to study immunogenicity because they have less of the tumour burden around, they re in better shape and they have fewer concomitant illnesses. This needs to be considered when a biosimilar sets up its pivotal study. 4 Table 3. Selecting sensitive populations for biosimilar monoclonal antibody studies in oncology 5 Topic Metastatic (palliative) Neo-Adjuvant/Adjuvant (curative) PK (-) Affected by patients status and tumour burden (+) Homogeneous population can be selected PD (-) Clinically validated PD marker not available (-) Clinically validated PD marker not available Clinical efficacy/ safety Immunogenicity (-) Population with heterogeneous characteristics affecting final clinical outcome. Need to control and stratify for multiple factors (e.g. prior use of chemotherapy, performance status). Difficult to select homogeneous group (-) Immuno compromised patients with immune system affected by performance status and concomitant chemotherapies received What are the sensitive endpoints for oncology? (+) Baseline patient characteristics allow to select homogeneous populations not confounded by external factors (+) Immune system impaired during chemotherapy cycles, but would likely recover to normal status after that period The need for biosimilar companies to identify the innovator experience and what the innovator trials have shown was emphasised by Dr Scappaticci. Using a summary of different response rates for several clinical studies completed in lymphoma and breast cancer (Table 4) he highlighted the most sensitive populations for biosimilar companies to set up equivalence trials. 4,5

6 9 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 10 Table 4. Response rates in lymphoma and breast cancer 5 Indication ORR control ORR active Effect size Reference NHL follicular induction (CHOP) 90% 96% 6% SPC (GLSG) Hiddemann NHL follicular induction (CVP) 10% 41% 31% SPC (CR) NHL follicular relapsed (CHOP) 74% 87% 13% SPC NHL DLBCL induction 76% 84% 8% SPC (CR) CLL 72% 86% 14% SPC Her 2 Neo adjuvant [(t)pcr] 21% 40% 19% NOAH Study Her 2 MBC 34% 61% 27% SPC You can see that in some settings there s very little difference in response rate between the active arm (the innovator arm) and the placebo arm. NHL follicular induction with CHOP, for example, would not be a smart place to do an equivalence study. Whereas with NHL follicular induction using CVP there is a 31% difference in response rate - so this may be a more practical setting to set up an equivalence trial. 4,5 Dr Scappaticci went on to highlight that if a biosimilar manufacturer set up a study in a population without sufficient sensitivity it would result in impractically large sample sizes per group. 4,5 The importance of the clinical setting in setting up these biosimilar studies is paramount. 4 CASE study: Clinical experience of two anti-cd20 monoclonal antibodies in rheumatoid arthritis 4,5 Dr Scappaticci presented a case study involving rituximab and a humanised version of rituximab called ocrelizumab. Both are monoclonal antibodies directed against CD20 positive B cells in the treatment of rheumatoid arthritis and both were developed by Roche. The two monoclonal antibodies were believed to be very similar until a serious infection safety signal was discovered late in the Phase III programme resulting in the termination of ocrelizumab development in rheumatoid arthritis. 4,5 The Phase III development programme for ocrelizumab was vast with four trials involving over 2,700 patients and two doses of ocrelizumab. Ocrelizumab showed consistent numerical increases in serious infection rates with the 500mg x 2 dose versus placebo in most trials. This was not observed with either dose of rituximab studied (500mg x 2 and 1000mg x 2) and was not predictable based on non-clinical and molecular data. The aetiology of the safety signal remains unclear. 4 Dr Scappaticci summarised: This was totally unpredictable and that is one of the lessons we learned. Even though we thought the non-clinical part of this development was very similar. The only difference was that one was a humanised monoclonal antibody to try to prevent the infusion related reactions. This safety signal was discovered at the high dose and we still don t know why that happened. It certainly wasn t predictable from the phase II experience of ocrelizumab. It highlights that phase III studies are so important in developing biologics and there s really no way of short cutting this from quality or nonclinical data. 4 Key learnings: 5 Roche had extensive experience with rituximab and was able to fully apply this knowledge to the development of ocrelizumab The serious infection safety signal encountered with ocrelizumab was unexpected, unpredictable and only occurred late in a large Phase III programme Phase III is paramount to understanding safety in the biologic and biosimilars will be no exception to this. 4 Pharmacovigilance: EMA sets high standards for biosimilar monoclonal antibodies Pharmacovigilance is the safety control procedure which medicines are subject to before, during and after regulatory approval. It is an important aspect of development of any biologic as safety needs to be understood both in the development and in the post-marketing setting. The ocrelizumab case study above highlights the importance of pharmacovigilance during the development of a biologic, particularly given the immunogenic potential of biologic products. Dr Schreitmüeller also emphasised the importance of robust pharmacovigilance for biologics in the post marketing setting citing the prominent example of epoetin-alfa and the formation of anti-drug antibodies leading to serious cases of pure red cell aplasia. We don t know the exact reason this occurred. There are many speculations many theories around but really there is no proper route cause analysis. 4 Dr Scappaticci commented on the EMA guidance for manufacturers of biosimilar monoclonal antibodies: What s been suggested in the guidance is that it s highly encouraged that biosimilar companies develop studies such as registries post marketing to further understand the safety. They ve even indicated that the pharmacovigilance programme of biosimilars may have to exceed that put in place by the innovator because they re going to have limited data and they need to set up a rigorous pharmacovigilance programme. 4 In addition Dr Scappaticci highlighted the need for biosimilar monoclonal antibodies to have a unique identity and for prescriptions to be written using the brand name, rather than generically, to allow for traceability to a patient level. He also emphasised the importance of accurate labelling for biosimilar monoclonal antibodies. 4 The labelling of biosimilar antibodies has to be clear and transparent as to what data was generated by the biosimilar and what data was referenced to the innovator. 4

7 11 The case for biosimilar monoclonal antibodies: Ask the experts biosimilar speaker tour 12 Extrapolating data across indications in a biosimilar market Extrapolation of data from one indication to another is becoming a hotly debated topic in the biosimilar arena. In a generic market for small molecule or chemical medicines, extrapolation of data to further indications is commonplace and generally accepted based on the innovator product and the generic containing identical active ingredients. It allows the generic manufacturer to save costs by not having to replicate clinical data in therapeutic areas already studied and approved during the innovators development and post-marketing programme. Three issues are at the centre of the extrapolation debate in the biotherapeutics market: Biosimilars are not identical copies of their reference biologic products Patient safety must be protected given the potential for immunogenic reactions with biotherapeutics products The mode of action of many biologics, particularly the more complex monoclonal antibodies, is often not fully understood and may differ across indications What do the new EMA guidelines for biosimilar monoclonal antibodies state? Although the EMA have not ruled out the possibility for biosimilar manufacturers to extrapolate data across indications, the guidance requires adequate justification based on the overall evidence provided in the comparability exercise. Additionally, the EMA acknowledges that the scientific justification for extrapolating data across indications when the reference product is licenced both as an immunomodulator and as an anticancer antibody will be more challenging. 1 Rituximab, for example, is approved as an immunomodulator in rheumatoid arthritis and as a cytotoxic in lymphoma. Dr Scappaticci explains: What the European guidance has said is that when you have this type of difference in the mechanism of action it would be very challenging to extrapolate from one of these indications to the other without having the clinical data. This is what the regulators are saying. This is going to be key. This mode of action is an important aspect of extrapolation. 4 Fifteen countries across Europe have introduced legislation to prevent automatic substitution of biological medicines by biosimilars. 5 Dr Scappaticci added that interchangeability will likely require additional clinical data by the FDA, although details are yet to be confirmed. 5 In New Zealand, consensus regarding the interchangeability of a biosimilar medicine and its reference product has yet to be reached. MedSafe advise the prescribing physician to take this into account when considering interchanging medicines. 6 So you can see how these biologic products, these biosimilars are different. They re not generics generics are identical copies. Biosimilars are similar they can never be identical. The reason they can never be identical is because they start from different source materials - different cell lines; they have different manufacturing processes these products can never be identical to their innovators and so all these issues have to be considered. 4 Why is demonstration of clinical similarity such a challenge for biosimilar antibodies in oncology? The key point about why it s been a challenge to develop biosimilar antibodies is really that the mode of action of these products is complex. Monoclonal antibodies such as rituximab may have three different mechanisms of action it could be inducing ADCC; it could be generating complement mediated lysis; it could be causing apoptosis many different mechanisms that could be different in different indications. 4 What does the FDA say about extrapolation? Dr Scappaticci went on to highlight similarity between the EMA guidance and draft FDA guidance on biosimilars. The FDA also believes that the mode of action is important when considering extrapolation. In particular, the target receptor activity needs to be well understood and the pharmacodynamic markers that do exist will be important in understanding mode of action. Safety has to be considered in each indication and differences in immunogenicity need to be considered. For example in rheumatoid arthritis the immunogenicity profile is going to be a lot different because these patients are hyper-stimulated with regard to their immune system, whereas with oncology it s a different situation so that has to be considered. 4 Extrapolation of data across indications is going to be difficult without good scientific justification and a good understanding of mode of action and safety across the board. 4 Interchangeability The EMA is clear that biosimilars cannot be considered identical to their biological reference products and that the decision to treat a patient with either should be made by a qualified healthcare professional. 15 The EMA also note in the recent guidance for biosimilar monoclonal antibodies that switching and interchanging of medicines might occur within the course of a patient s treatment. Applicants are therefore recommended to follow further development in the field and consider these aspects as part of the risk management plan. 1

8 13 References 1. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues. Available from < WC pdf>. [Accessed 23 August 2012]. 2. EMA. Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. Available from < [Accessed 23 August 2012]. 3. Schreitmüeller T. Biosimilar Regulations Rationales and Requirements. Roche Products (New Zealand) Ltd Biosimilar speaker presentation. July 2012 Auckland, New Zealand. 4. Roche Data on File BIO Scappaticci F. Clinical Challenges for Establishing Biosimilarity for Monoclonal Antibodies. Roche Products (New Zealand) Ltd Biosimilar speaker presentation. July 2012 Wellington, New Zealand. 6. MedSafe information for health professionals Regulatory issues biosimilars. Available from < profs/riss/biosimilars.asp>. [Accessed 23 August 2012]. 7. MedSafe Regulatory information product/application search. Available from < DbSearch.asp>. [Accessed on 23 August 2012]. 8. PHARMAC Notification. Decision to award sole supply for, and widen funded access to filgrastim. Available from < [Accessed 23 August 2012]. 9. Hicks N. Briefing paper on biosimilar medicines. International Alliance of Patients Organizations. IAPO, WHO. Guidelines on evaluation of similar biotherapeutic products (SBPs). Available from < areas/biological_therapeutics/biotherapeutics_for_web_22april2010.pdf>. [Accessed 23 August 2012]. 11. Roger SD. Biosimilars: current status and future directions. Expert Opin Biol Ther 2010; 10(7): Niebecker R, Kloft C. Safety of therapeutic monoclonal antibodies. Curr Drug Saf 2010; 5(4): EMA. Guideline on similar biological medicinal products. Available from < document_library/scientific_guideline/2009/09/wc pdf>. [Accessed 23 August 2012]. 14. EMA. European public assessment reports. Available from < edicines%2flanding%2fepar_search.jsp&mid=wc0b01ac058001d124&searchtab=searchbyauthtype&alreadyloaded=t rue&isnewquery=true&status=authorised&keyword=enter+keywords&searchtype=name&taxonomypath=&treenumber =&searchgenerictype=biosimilars&genericskeywordsearch=submit>. [Accessed 23 August 2012]. 15. EMA. Questions and Answers on biosimilar medicines (similar biological medicinal products). Available from < [Accessed 23 August 2012]. Healthcare professional briefings Wellington: Monday 23 July 2012 Horne Lecture Theatre, Wellington Hospital Auckland: Tuesday 24 July 2012 Fisher & Paykel Healthcare Clinical Education Centre, Auckland City Hospital This presentation was sponsored by Roche Products (New Zealand) Ltd. Products mentioned in the presentation are prescription medicines and detailed prescribing information is available at Some medicines or indications may not be currently licensed in New Zealand.

9 Roche Products (New Zealand) Limited PO Box , Newmarket, Auckland 1149 Toll free: SAP# /DA0513KS/2013MAR